[{"volume":12,"license":"https://creativecommons.org/licenses/by/4.0/","file":[{"success":1,"file_id":"12450","checksum":"efc7edf9f626af31853790c5b598a68c","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"2022_FrontiersOntology_Basilico.pdf","date_created":"2023-01-30T10:25:21Z","file_size":13588502,"date_updated":"2023-01-30T10:25:21Z","creator":"dernst"}],"language":[{"iso":"eng"}],"publication_identifier":{"issn":["2234-943X"]},"publication_status":"published","month":"08","intvolume":" 12","scopus_import":"1","oa_version":"Published Version","pmid":1,"abstract":[{"lang":"eng","text":"The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial–mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear. We have previously showed that certain substrate stiffness can selectively stimulate human GBM U251-MG and GL15 glioblastoma cell lines motility. The present study unifies several known EMT mediators to uncover the reason of the regulation and response to these stiffnesses. Our results revealed that changing the rigidity of the mechanical environment tuned the response of both cell lines through change in morphological features, epithelial-mesenchymal markers (E-, N-Cadherin), EGFR and ROS expressions in an interrelated manner. Specifically, a stiffer microenvironment induced a mesenchymal cell shape, a more fragmented morphology, higher intracellular cytosolic ROS expression and lower mitochondrial ROS. Finally, we observed that cells more motile showed a more depolarized mitochondrial membrane potential. Unravelling the process that regulates GBM cells’ infiltrative behavior could provide new opportunities for identification of new targets and less invasive approaches for treatment."}],"department":[{"_id":"GaNo"}],"file_date_updated":"2023-01-30T10:25:21Z","ddc":["570"],"date_updated":"2023-08-04T09:54:16Z","status":"public","keyword":["Cancer Research","Oncology"],"type":"journal_article","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"_id":"12268","doi":"10.3389/fonc.2022.983507","date_published":"2022-08-25T00:00:00Z","date_created":"2023-01-16T10:00:28Z","day":"25","publication":"Frontiers in Oncology","isi":1,"has_accepted_license":"1","year":"2022","publisher":"Frontiers Media","quality_controlled":"1","oa":1,"acknowledgement":"The research leading to these results has received funding from AIRC under IG 2021 - ID. 26328 project – P.I. Cortese Barbara and AIRC under MFAG 2015 - ID. 16803 project – “P.I. Cortese Barbara”. The authors are also grateful to the ”Tecnopolo per la medicina di precisione” (TecnoMed Puglia) - Regione Puglia: DGR n.2117 del 21/11/2018, CUP: B84I18000540002 and “Tecnopolo di Nanotecnologia e Fotonica per la medicina di precisione” (TECNOMED) - FISR/MIUR-CNR: delibera CIPE n.3449 del 7-08-2017, CUP: B83B17000010001.\r\nWe thank Dr. Francesca Pagani for useful technical support. We thank also Irene Iacuitto, Giovanna Loffredo and Manuela Marchetti for practical administrative support.","title":"Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells","author":[{"orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico","first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425"},{"first_name":"Ilaria Elena","full_name":"Palamà, Ilaria Elena","last_name":"Palamà"},{"first_name":"Stefania","last_name":"D’Amone","full_name":"D’Amone, Stefania"},{"first_name":"Clotilde","last_name":"Lauro","full_name":"Lauro, Clotilde"},{"full_name":"Rosito, Maria","last_name":"Rosito","first_name":"Maria"},{"first_name":"Maddalena","full_name":"Grieco, Maddalena","last_name":"Grieco"},{"full_name":"Ratano, Patrizia","last_name":"Ratano","first_name":"Patrizia"},{"last_name":"Cordella","full_name":"Cordella, Federica","first_name":"Federica"},{"full_name":"Sanchini, Caterina","last_name":"Sanchini","first_name":"Caterina"},{"first_name":"Silvia","full_name":"Di Angelantonio, Silvia","last_name":"Di Angelantonio"},{"full_name":"Ragozzino, Davide","last_name":"Ragozzino","first_name":"Davide"},{"first_name":"Mariafrancesca","full_name":"Cascione, Mariafrancesca","last_name":"Cascione"},{"first_name":"Giuseppe","last_name":"Gigli","full_name":"Gigli, Giuseppe"},{"first_name":"Barbara","last_name":"Cortese","full_name":"Cortese, Barbara"}],"external_id":{"isi":["000856524900001"],"pmid":["36091138"]},"article_processing_charge":"No","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"ieee":"B. Basilico et al., “Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells,” Frontiers in Oncology, vol. 12. Frontiers Media, 2022.","short":"B. Basilico, I.E. Palamà, S. D’Amone, C. Lauro, M. Rosito, M. Grieco, P. Ratano, F. Cordella, C. Sanchini, S. Di Angelantonio, D. Ragozzino, M. Cascione, G. Gigli, B. Cortese, Frontiers in Oncology 12 (2022).","ama":"Basilico B, Palamà IE, D’Amone S, et al. Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. 2022;12. doi:10.3389/fonc.2022.983507","apa":"Basilico, B., Palamà, I. E., D’Amone, S., Lauro, C., Rosito, M., Grieco, M., … Cortese, B. (2022). Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. Frontiers Media. https://doi.org/10.3389/fonc.2022.983507","mla":"Basilico, Bernadette, et al. “Substrate Stiffness Effect on Molecular Crosstalk of Epithelial-Mesenchymal Transition Mediators of Human Glioblastoma Cells.” Frontiers in Oncology, vol. 12, 983507, Frontiers Media, 2022, doi:10.3389/fonc.2022.983507.","ista":"Basilico B, Palamà IE, D’Amone S, Lauro C, Rosito M, Grieco M, Ratano P, Cordella F, Sanchini C, Di Angelantonio S, Ragozzino D, Cascione M, Gigli G, Cortese B. 2022. Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. 12, 983507.","chicago":"Basilico, Bernadette, Ilaria Elena Palamà, Stefania D’Amone, Clotilde Lauro, Maria Rosito, Maddalena Grieco, Patrizia Ratano, et al. “Substrate Stiffness Effect on Molecular Crosstalk of Epithelial-Mesenchymal Transition Mediators of Human Glioblastoma Cells.” Frontiers in Oncology. Frontiers Media, 2022. https://doi.org/10.3389/fonc.2022.983507."},"article_number":"983507"},{"date_updated":"2023-09-05T16:01:23Z","ddc":["570"],"file_date_updated":"2022-03-04T08:55:27Z","department":[{"_id":"GaNo"}],"_id":"10818","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","image":"/images/cc_by_nc.png","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","short":"CC BY-NC (4.0)"},"article_type":"original","type":"journal_article","keyword":["Cellular and Molecular Neuroscience","Neurology"],"status":"public","publication_status":"published","publication_identifier":{"issn":["0894-1491"],"eissn":["1098-1136"]},"language":[{"iso":"eng"}],"file":[{"file_id":"10819","checksum":"f10a897290e66c0a062e04ba91db6c17","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","date_created":"2022-03-04T08:55:27Z","file_name":"2021_Glia_Basilico.pdf","date_updated":"2022-03-04T08:55:27Z","file_size":5340294,"creator":"dernst"}],"license":"https://creativecommons.org/licenses/by-nc/4.0/","issue":"1","volume":70,"abstract":[{"lang":"eng","text":"Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses."}],"oa_version":"Published Version","pmid":1,"scopus_import":"1","intvolume":" 70","month":"01","citation":{"mla":"Basilico, Bernadette, et al. “Microglia Control Glutamatergic Synapses in the Adult Mouse Hippocampus.” Glia, vol. 70, no. 1, Wiley, 2022, pp. 173–95, doi:10.1002/glia.24101.","ama":"Basilico B, Ferrucci L, Ratano P, et al. Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. 2022;70(1):173-195. doi:10.1002/glia.24101","apa":"Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., … Ragozzino, D. (2022). Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. Wiley. https://doi.org/10.1002/glia.24101","short":"B. Basilico, L. Ferrucci, P. Ratano, M.T. Golia, A. Grimaldi, M. Rosito, V. Ferretti, I. Reverte, C. Sanchini, M.C. Marrone, M. Giubettini, V. De Turris, D. Salerno, S. Garofalo, M. St‐Pierre, M. Carrier, M. Renzi, F. Pagani, B. Modi, M. Raspa, F. Scavizzi, C.T. Gross, S. Marinelli, M. Tremblay, D. Caprioli, L. Maggi, C. Limatola, S. Di Angelantonio, D. Ragozzino, Glia 70 (2022) 173–195.","ieee":"B. Basilico et al., “Microglia control glutamatergic synapses in the adult mouse hippocampus,” Glia, vol. 70, no. 1. Wiley, pp. 173–195, 2022.","chicago":"Basilico, Bernadette, Laura Ferrucci, Patrizia Ratano, Maria T. Golia, Alfonso Grimaldi, Maria Rosito, Valentina Ferretti, et al. “Microglia Control Glutamatergic Synapses in the Adult Mouse Hippocampus.” Glia. Wiley, 2022. https://doi.org/10.1002/glia.24101.","ista":"Basilico B, Ferrucci L, Ratano P, Golia MT, Grimaldi A, Rosito M, Ferretti V, Reverte I, Sanchini C, Marrone MC, Giubettini M, De Turris V, Salerno D, Garofalo S, St‐Pierre M, Carrier M, Renzi M, Pagani F, Modi B, Raspa M, Scavizzi F, Gross CT, Marinelli S, Tremblay M, Caprioli D, Maggi L, Limatola C, Di Angelantonio S, Ragozzino D. 2022. Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. 70(1), 173–195."},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_processing_charge":"No","external_id":{"pmid":["34661306"],"isi":["000708025800001"]},"author":[{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","last_name":"Basilico","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173"},{"first_name":"Laura","last_name":"Ferrucci","full_name":"Ferrucci, Laura"},{"first_name":"Patrizia","last_name":"Ratano","full_name":"Ratano, Patrizia"},{"first_name":"Maria T.","last_name":"Golia","full_name":"Golia, Maria T."},{"last_name":"Grimaldi","full_name":"Grimaldi, Alfonso","first_name":"Alfonso"},{"full_name":"Rosito, Maria","last_name":"Rosito","first_name":"Maria"},{"first_name":"Valentina","last_name":"Ferretti","full_name":"Ferretti, Valentina"},{"last_name":"Reverte","full_name":"Reverte, Ingrid","first_name":"Ingrid"},{"first_name":"Caterina","full_name":"Sanchini, Caterina","last_name":"Sanchini"},{"last_name":"Marrone","full_name":"Marrone, Maria C.","first_name":"Maria C."},{"first_name":"Maria","full_name":"Giubettini, Maria","last_name":"Giubettini"},{"full_name":"De Turris, Valeria","last_name":"De Turris","first_name":"Valeria"},{"last_name":"Salerno","full_name":"Salerno, Debora","first_name":"Debora"},{"first_name":"Stefano","last_name":"Garofalo","full_name":"Garofalo, Stefano"},{"full_name":"St‐Pierre, Marie‐Kim","last_name":"St‐Pierre","first_name":"Marie‐Kim"},{"full_name":"Carrier, Micael","last_name":"Carrier","first_name":"Micael"},{"first_name":"Massimiliano","last_name":"Renzi","full_name":"Renzi, Massimiliano"},{"full_name":"Pagani, Francesca","last_name":"Pagani","first_name":"Francesca"},{"first_name":"Brijesh","full_name":"Modi, Brijesh","last_name":"Modi"},{"last_name":"Raspa","full_name":"Raspa, Marcello","first_name":"Marcello"},{"first_name":"Ferdinando","last_name":"Scavizzi","full_name":"Scavizzi, Ferdinando"},{"last_name":"Gross","full_name":"Gross, Cornelius T.","first_name":"Cornelius T."},{"full_name":"Marinelli, Silvia","last_name":"Marinelli","first_name":"Silvia"},{"last_name":"Tremblay","full_name":"Tremblay, Marie‐Ève","first_name":"Marie‐Ève"},{"full_name":"Caprioli, Daniele","last_name":"Caprioli","first_name":"Daniele"},{"full_name":"Maggi, Laura","last_name":"Maggi","first_name":"Laura"},{"last_name":"Limatola","full_name":"Limatola, Cristina","first_name":"Cristina"},{"last_name":"Di Angelantonio","full_name":"Di Angelantonio, Silvia","first_name":"Silvia"},{"first_name":"Davide","last_name":"Ragozzino","full_name":"Ragozzino, Davide"}],"title":"Microglia control glutamatergic synapses in the adult mouse hippocampus","year":"2022","isi":1,"has_accepted_license":"1","publication":"Glia","day":"01","page":"173-195","date_created":"2022-03-04T08:53:37Z","date_published":"2022-01-01T00:00:00Z","doi":"10.1002/glia.24101","acknowledgement":"The work was supported by a grant from MIUR (PRIN 2017HPTFFC_003) to Davide Ragozzino and in part by funds to Silvia Di Angelantonio (CrestOptics-IIT JointLab for Advanced Microscopy) and Daniele Caprioli (Istituto Pasteur-Fondazione Cenci Bolognetti). Bernadette Basilico, and Laura Ferrucci were supported by the PhD program in Clinical-Experimental Neuroscience and Psychiatry, Sapienza University, Rome; Caterina Sanchini was supported by the PhD program in Life Science, Sapienza University, Rome and by the Italian Institute of Technology, Rome. The authors thank Alessandro Felici, Claudia Valeri, Arsenio Armagno, and Senthilkumar Deivasigamani for help with animal husbandry and transgenic colonies management. They also wish to thank Piotr Bregestovski and Michal Schwartz for helpful discussions and criticism. PLX5622 was provided under Materials Transfer Agreement by Plexxikon Inc. (Berkeley, CA). Open Access Funding provided by Universita degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.","oa":1,"quality_controlled":"1","publisher":"Wiley"},{"_id":"11943","type":"preprint","status":"public","citation":{"mla":"Velicky, Philipp, et al. “Saturated Reconstruction of Living Brain Tissue.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2022.03.16.484431.","apa":"Velicky, P., Miguel Villalba, E., Michalska, J. M., Wei, D., Lin, Z., Watson, J., … Danzl, J. G. (n.d.). Saturated reconstruction of living brain tissue. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2022.03.16.484431","ama":"Velicky P, Miguel Villalba E, Michalska JM, et al. Saturated reconstruction of living brain tissue. bioRxiv. doi:10.1101/2022.03.16.484431","ieee":"P. Velicky et al., “Saturated reconstruction of living brain tissue,” bioRxiv. Cold Spring Harbor Laboratory.","short":"P. Velicky, E. Miguel Villalba, J.M. Michalska, D. Wei, Z. Lin, J. Watson, J. Troidl, J. Beyer, Y. Ben Simon, C.M. Sommer, W. Jahr, A. Cenameri, J. Broichhagen, S.G.N. Grant, P.M. Jonas, G. Novarino, H. Pfister, B. Bickel, J.G. Danzl, BioRxiv (n.d.).","chicago":"Velicky, Philipp, Eder Miguel Villalba, Julia M Michalska, Donglai Wei, Zudi Lin, Jake Watson, Jakob Troidl, et al. “Saturated Reconstruction of Living Brain Tissue.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2022.03.16.484431.","ista":"Velicky P, Miguel Villalba E, Michalska JM, Wei D, Lin Z, Watson J, Troidl J, Beyer J, Ben Simon Y, Sommer CM, Jahr W, Cenameri A, Broichhagen J, Grant SGN, Jonas PM, Novarino G, Pfister H, Bickel B, Danzl JG. Saturated reconstruction of living brain tissue. bioRxiv, 10.1101/2022.03.16.484431."},"date_updated":"2024-03-27T23:30:20Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","author":[{"full_name":"Velicky, Philipp","orcid":"0000-0002-2340-7431","last_name":"Velicky","first_name":"Philipp","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Miguel Villalba","orcid":"0000-0001-5665-0430","full_name":"Miguel Villalba, Eder","first_name":"Eder","id":"3FB91342-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Michalska","full_name":"Michalska, Julia M","orcid":"0000-0003-3862-1235","first_name":"Julia M","id":"443DB6DE-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Donglai","last_name":"Wei","full_name":"Wei, Donglai"},{"first_name":"Zudi","last_name":"Lin","full_name":"Lin, Zudi"},{"last_name":"Watson","full_name":"Watson, Jake","orcid":"0000-0002-8698-3823","id":"63836096-4690-11EA-BD4E-32803DDC885E","first_name":"Jake"},{"first_name":"Jakob","last_name":"Troidl","full_name":"Troidl, Jakob"},{"first_name":"Johanna","full_name":"Beyer, Johanna","last_name":"Beyer"},{"full_name":"Ben Simon, Yoav","last_name":"Ben Simon","id":"43DF3136-F248-11E8-B48F-1D18A9856A87","first_name":"Yoav"},{"last_name":"Sommer","full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Jahr, Wiebke","last_name":"Jahr","first_name":"Wiebke","id":"425C1CE8-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Alban","id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban","last_name":"Cenameri"},{"first_name":"Johannes","last_name":"Broichhagen","full_name":"Broichhagen, Johannes"},{"first_name":"Seth G. N.","full_name":"Grant, Seth G. N.","last_name":"Grant"},{"id":"353C1B58-F248-11E8-B48F-1D18A9856A87","first_name":"Peter M","last_name":"Jonas","orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M"},{"orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Pfister","full_name":"Pfister, Hanspeter","first_name":"Hanspeter"},{"id":"49876194-F248-11E8-B48F-1D18A9856A87","first_name":"Bernd","last_name":"Bickel","full_name":"Bickel, Bernd","orcid":"0000-0001-6511-9385"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973"}],"title":"Saturated reconstruction of living brain tissue","department":[{"_id":"PeJo"},{"_id":"GaNo"},{"_id":"BeBi"},{"_id":"JoDa"}],"abstract":[{"lang":"eng","text":"Complex wiring between neurons underlies the information-processing network enabling all brain functions, including cognition and memory. For understanding how the network is structured, processes information, and changes over time, comprehensive visualization of the architecture of living brain tissue with its cellular and molecular components would open up major opportunities. However, electron microscopy (EM) provides nanometre-scale resolution required for full in-silico reconstruction1–5, yet is limited to fixed specimens and static representations. Light microscopy allows live observation, with super-resolution approaches6–12 facilitating nanoscale visualization, but comprehensive 3D-reconstruction of living brain tissue has been hindered by tissue photo-burden, photobleaching, insufficient 3D-resolution, and inadequate signal-to-noise ratio (SNR). Here we demonstrate saturated reconstruction of living brain tissue. We developed an integrated imaging and analysis technology, adapting stimulated emission depletion (STED) microscopy6,13 in extracellularly labelled tissue14 for high SNR and near-isotropic resolution. Centrally, a two-stage deep-learning approach leveraged previously obtained information on sample structure to drastically reduce photo-burden and enable automated volumetric reconstruction down to single synapse level. Live reconstruction provides unbiased analysis of tissue architecture across time in relation to functional activity and targeted activation, and contextual understanding of molecular labelling. This adoptable technology will facilitate novel insights into the dynamic functional architecture of living brain tissue."}],"oa_version":"Preprint","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2022.03.16.484431"}],"oa":1,"publisher":"Cold Spring Harbor Laboratory","month":"05","publication_status":"submitted","year":"2022","language":[{"iso":"eng"}],"publication":"bioRxiv","day":"09","date_created":"2022-08-23T11:07:59Z","related_material":{"record":[{"relation":"dissertation_contains","id":"12470","status":"public"}]},"doi":"10.1101/2022.03.16.484431","date_published":"2022-05-09T00:00:00Z"},{"publication":"bioRxiv","language":[{"iso":"eng"}],"day":"18","publication_status":"submitted","year":"2022","date_created":"2022-08-24T08:24:52Z","related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"12470"}]},"doi":"10.1101/2022.08.17.504272","date_published":"2022-08-18T00:00:00Z","oa_version":"Preprint","abstract":[{"text":"Mapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.","lang":"eng"}],"month":"08","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1101/2022.08.17.504272"}],"oa":1,"publisher":"Cold Spring Harbor Laboratory","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"chicago":"Michalska, Julia M, Julia Lyudchik, Philipp Velicky, Hana Korinkova, Jake Watson, Alban Cenameri, Christoph M Sommer, et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2022.08.17.504272.","ista":"Michalska JM, Lyudchik J, Velicky P, Korinkova H, Watson J, Cenameri A, Sommer CM, Venturino A, Roessler K, Czech T, Siegert S, Novarino G, Jonas PM, Danzl JG. Uncovering brain tissue architecture across scales with super-resolution light microscopy. bioRxiv, 10.1101/2022.08.17.504272.","mla":"Michalska, Julia M., et al. “Uncovering Brain Tissue Architecture across Scales with Super-Resolution Light Microscopy.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2022.08.17.504272.","ieee":"J. M. Michalska et al., “Uncovering brain tissue architecture across scales with super-resolution light microscopy,” bioRxiv. Cold Spring Harbor Laboratory.","short":"J.M. Michalska, J. Lyudchik, P. Velicky, H. Korinkova, J. Watson, A. Cenameri, C.M. Sommer, A. Venturino, K. Roessler, T. Czech, S. Siegert, G. Novarino, P.M. Jonas, J.G. Danzl, BioRxiv (n.d.).","ama":"Michalska JM, Lyudchik J, Velicky P, et al. Uncovering brain tissue architecture across scales with super-resolution light microscopy. bioRxiv. doi:10.1101/2022.08.17.504272","apa":"Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J., Cenameri, A., … Danzl, J. G. (n.d.). Uncovering brain tissue architecture across scales with super-resolution light microscopy. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2022.08.17.504272"},"date_updated":"2024-03-27T23:30:20Z","title":"Uncovering brain tissue architecture across scales with super-resolution light microscopy","department":[{"_id":"SaSi"},{"_id":"GaNo"},{"_id":"PeJo"},{"_id":"JoDa"}],"article_processing_charge":"No","author":[{"id":"443DB6DE-F248-11E8-B48F-1D18A9856A87","first_name":"Julia M","full_name":"Michalska, Julia M","orcid":"0000-0003-3862-1235","last_name":"Michalska"},{"last_name":"Lyudchik","full_name":"Lyudchik, Julia","first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Philipp","id":"39BDC62C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-2340-7431","full_name":"Velicky, Philipp","last_name":"Velicky"},{"id":"ee3cb6ca-ec98-11ea-ae11-ff703e2254ed","first_name":"Hana","full_name":"Korinkova, Hana","last_name":"Korinkova"},{"last_name":"Watson","orcid":"0000-0002-8698-3823","full_name":"Watson, Jake","first_name":"Jake","id":"63836096-4690-11EA-BD4E-32803DDC885E"},{"first_name":"Alban","id":"9ac8f577-2357-11eb-997a-e566c5550886","full_name":"Cenameri, Alban","last_name":"Cenameri"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro","last_name":"Venturino"},{"first_name":"Karl","full_name":"Roessler, Karl","last_name":"Roessler"},{"full_name":"Czech, Thomas","last_name":"Czech","first_name":"Thomas"},{"last_name":"Siegert","full_name":"Siegert, Sandra","orcid":"0000-0001-8635-0877","first_name":"Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"},{"first_name":"Peter M","id":"353C1B58-F248-11E8-B48F-1D18A9856A87","last_name":"Jonas","orcid":"0000-0001-5001-4804","full_name":"Jonas, Peter M"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","last_name":"Danzl"}],"_id":"11950","status":"public","type":"preprint"},{"ddc":["570"],"date_updated":"2024-03-27T23:30:44Z","department":[{"_id":"JoDa"},{"_id":"GaNo"}],"file_date_updated":"2022-04-15T09:06:25Z","_id":"11160","keyword":["General Biochemistry","Genetics and Molecular Biology"],"status":"public","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","language":[{"iso":"eng"}],"file":[{"success":1,"checksum":"b4e8d68f0268dec499af333e6fd5d8e1","file_id":"11164","relation":"main_file","access_level":"open_access","content_type":"application/pdf","file_name":"2022_CellReports_Villa.pdf","date_created":"2022-04-15T09:06:25Z","creator":"dernst","file_size":"7808644","date_updated":"2022-04-15T09:06:25Z"}],"publication_status":"published","publication_identifier":{"issn":["2211-1247"]},"ec_funded":1,"related_material":{"record":[{"id":"12364","status":"public","relation":"dissertation_contains"}]},"volume":39,"issue":"1","pmid":1,"oa_version":"Published Version","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"abstract":[{"lang":"eng","text":"Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling."}],"intvolume":" 39","month":"04","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports, vol. 39, no. 1, 110615, Elsevier, 2022, doi:10.1016/j.celrep.2022.110615.","short":"C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco, A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer, M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).","ieee":"C. E. Villa et al., “CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories,” Cell Reports, vol. 39, no. 1. Elsevier, 2022.","ama":"Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 2022;39(1). doi:10.1016/j.celrep.2022.110615","apa":"Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco, R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2022.110615","chicago":"Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon, Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports. Elsevier, 2022. https://doi.org/10.1016/j.celrep.2022.110615.","ista":"Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ, Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG, Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615."},"title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories","external_id":{"pmid":["35385734"],"isi":["000785983900003"]},"article_processing_charge":"Yes","author":[{"first_name":"Carlo Emanuele","last_name":"Villa","full_name":"Villa, Carlo Emanuele"},{"first_name":"Cristina","full_name":"Cheroni, Cristina","last_name":"Cheroni"},{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph","last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph"},{"last_name":"López-Tóbon","full_name":"López-Tóbon, Alejandro","first_name":"Alejandro"},{"first_name":"Bárbara","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","last_name":"Oliveira","full_name":"Oliveira, Bárbara"},{"id":"42C9F57E-F248-11E8-B48F-1D18A9856A87","first_name":"Roberto","full_name":"Sacco, Roberto","last_name":"Sacco"},{"full_name":"Yahya, Aysan Çerağ","last_name":"Yahya","first_name":"Aysan Çerağ","id":"365A65F8-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"full_name":"Gabriele, Michele","last_name":"Gabriele","first_name":"Michele"},{"id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","first_name":"Mojtaba","last_name":"Tavakoli","full_name":"Tavakoli, Mojtaba","orcid":"0000-0002-7667-6854"},{"first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","last_name":"Lyudchik","full_name":"Lyudchik, Julia"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Gabitto, Mariano","last_name":"Gabitto","first_name":"Mariano"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","last_name":"Danzl"},{"last_name":"Testa","full_name":"Testa, Giuseppe","first_name":"Giuseppe"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"article_number":"110615","project":[{"grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"_id":"2690FEAC-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","grant_number":"I04205","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy"}],"publication":"Cell Reports","day":"05","year":"2022","isi":1,"has_accepted_license":"1","date_created":"2022-04-15T09:03:10Z","doi":"10.1016/j.celrep.2022.110615","date_published":"2022-04-05T00:00:00Z","acknowledgement":"We thank Farnaz Freeman for technical assistance. This research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This work supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs); the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele; and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures were created using BioRender.com.","oa":1,"quality_controlled":"1","publisher":"Elsevier"},{"project":[{"grant_number":"401299","name":"Probing development and reversibility of autism spectrum disorders","_id":"254BA948-B435-11E9-9278-68D0E5697425"},{"grant_number":"707964","name":"Critical windows and reversibility of ASD associated with mutations in chromatin remodelers","_id":"9B91375C-BA93-11EA-9121-9846C619BF3A"},{"name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508","_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","grant_number":"I04205","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy"}],"citation":{"ama":"Dotter C. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. 2022. doi:10.15479/at:ista:12094","apa":"Dotter, C. (2022). Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12094","ieee":"C. Dotter, “Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder,” Institute of Science and Technology Austria, 2022.","short":"C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022.","mla":"Dotter, Christoph. Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder. Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:12094.","ista":"Dotter C. 2022. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria.","chicago":"Dotter, Christoph. “Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:12094."},"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","article_processing_charge":"No","author":[{"last_name":"Dotter","full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph"}],"title":"Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder","oa":1,"publisher":"Institute of Science and Technology Austria","year":"2022","has_accepted_license":"1","day":"19","page":"152","date_created":"2023-01-24T13:09:57Z","doi":"10.15479/at:ista:12094","date_published":"2022-09-19T00:00:00Z","_id":"12364","type":"dissertation","status":"public","date_updated":"2023-11-16T13:10:22Z","supervisor":[{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"}],"ddc":["570"],"file_date_updated":"2023-09-20T22:30:03Z","department":[{"_id":"GradSch"},{"_id":"GaNo"}],"abstract":[{"text":"Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\u0002ized by behavioral symptoms such as problems in social communication and interaction, as\r\nwell as repetitive, restricted behaviors and interests. These disorders show a high degree\r\nof heritability and hundreds of risk genes have been identifed using high throughput\r\nsequencing technologies. This genetic heterogeneity has hampered eforts in understanding\r\nthe pathogenesis of ASD but at the same time given rise to the concept of convergent\r\nmechanisms. Previous studies have identifed that risk genes for ASD broadly converge\r\nonto specifc functional categories with transcriptional regulation being one of the biggest\r\ngroups. In this thesis, I focus on this subgroup of genes and investigate the gene regulatory\r\nconsequences of some of them in the context of neurodevelopment.\r\nFirst, we showed that mutations in the ASD and intellectual disability risk gene Setd5 lead\r\nto perturbations of gene regulatory programs in early cell fate specifcation. In addition,\r\nadult animals display abnormal learning behavior which is mirrored at the transcriptional\r\nlevel by altered activity dependent regulation of postsynaptic gene expression. Lastly,\r\nwe link the regulatory function of Setd5 to its interaction with the Paf1 and the NCoR\r\ncomplex.\r\nSecond, by modeling the heterozygous loss of the top ASD gene CHD8 in human cerebral\r\norganoids we demonstrate profound changes in the developmental trajectories of both\r\ninhibitory and excitatory neurons using single cell RNA-sequencing. While the former\r\nwere generated earlier in CHD8+/- organoids, the generation of the latter was shifted to\r\nlater times in favor of a prolonged progenitor expansion phase and ultimately increased\r\norganoid size.\r\nFinally, by modeling heterozygous mutations for four ASD associated chromatin modifers,\r\nASH1L, KDM6B, KMT5B, and SETD5 in human cortical spheroids we show evidence of\r\nregulatory convergence across three of those genes. We observe a shift from dorsal cortical\r\nexcitatory neuron fates towards partially ventralized cell types resembling cells from the\r\nlateral ganglionic eminence. As this project is still ongoing at the time of writing, future\r\nexperiments will aim at elucidating the regulatory mechanisms underlying this shift with\r\nthe aim of linking these three ASD risk genes through biological convergence.","lang":"eng"}],"oa_version":"Published Version","alternative_title":["ISTA Thesis"],"month":"09","publication_status":"published","degree_awarded":"PhD","publication_identifier":{"issn":["2663-337X"]},"language":[{"iso":"eng"}],"file":[{"creator":"cchlebak","date_updated":"2023-09-20T22:30:03Z","file_size":20457465,"date_created":"2023-01-24T13:15:45Z","file_name":"220923_Thesis_CDotter_Final.pdf","access_level":"open_access","relation":"main_file","content_type":"application/pdf","checksum":"896f4cac9adb6d3f26a6605772f4e1a3","file_id":"12365","embargo":"2023-09-19"},{"date_updated":"2023-09-20T22:30:03Z","file_size":22433512,"creator":"cchlebak","date_created":"2023-02-02T09:15:35Z","file_name":"latex_source_CDotter_Thesis_2022.zip","content_type":"application/x-zip-compressed","embargo_to":"open_access","access_level":"closed","relation":"source_file","checksum":"ad01bb20da163be6893b7af832e58419","file_id":"12482"}],"ec_funded":1,"related_material":{"record":[{"status":"public","id":"3","relation":"part_of_dissertation"},{"relation":"part_of_dissertation","status":"public","id":"11160"}]}},{"ddc":["570"],"date_updated":"2023-08-14T11:46:12Z","department":[{"_id":"GaNo"}],"file_date_updated":"2022-05-16T07:02:27Z","_id":"10281","status":"public","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_type":"original","type":"journal_article","language":[{"iso":"eng"}],"file":[{"date_created":"2022-05-16T07:02:27Z","file_name":"2021_Genes_Vasic.pdf","date_updated":"2022-05-16T07:02:27Z","file_size":1335308,"creator":"dernst","file_id":"11380","checksum":"256cb832a9c3051c7dc741f6423b8cbd","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file"}],"publication_status":"published","publication_identifier":{"eissn":["2073-4425"]},"ec_funded":1,"issue":"11","volume":12,"oa_version":"Published Version","abstract":[{"lang":"eng","text":"Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems"}],"intvolume":" 12","month":"10","alternative_title":["Special Issue \"From Genes to Therapy in Autism Spectrum Disorder\""],"scopus_import":"1","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"mla":"Vasic, Verica, et al. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes, vol. 12, no. 11, 1746, MDPI, 2021, doi:10.3390/genes12111746.","ama":"Vasic V, Jones MSO, Haslinger D, et al. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. 2021;12(11). doi:10.3390/genes12111746","apa":"Vasic, V., Jones, M. S. O., Haslinger, D., Knaus, L., Schmeisser, M. J., Novarino, G., & Chiocchetti, A. G. (2021). Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. MDPI. https://doi.org/10.3390/genes12111746","ieee":"V. Vasic et al., “Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment,” Genes, vol. 12, no. 11. MDPI, 2021.","short":"V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino, A.G. Chiocchetti, Genes 12 (2021).","chicago":"Vasic, Verica, Mattson S.O. Jones, Denise Haslinger, Lisa Knaus, Michael J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes. MDPI, 2021. https://doi.org/10.3390/genes12111746.","ista":"Vasic V, Jones MSO, Haslinger D, Knaus L, Schmeisser MJ, Novarino G, Chiocchetti AG. 2021. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. 12(11), 1746."},"title":"Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment","article_processing_charge":"No","external_id":{"isi":["000834044200002"]},"author":[{"full_name":"Vasic, Verica","last_name":"Vasic","first_name":"Verica"},{"first_name":"Mattson S.O.","last_name":"Jones","full_name":"Jones, Mattson S.O."},{"id":"76922BDA-3D3B-11EA-90BD-A44F3DDC885E","first_name":"Denise","full_name":"Haslinger, Denise","last_name":"Haslinger"},{"first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa","last_name":"Knaus"},{"full_name":"Schmeisser, Michael J.","last_name":"Schmeisser","first_name":"Michael J."},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"},{"first_name":"Andreas G.","last_name":"Chiocchetti","full_name":"Chiocchetti, Andreas G."}],"article_number":"1746","project":[{"grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425"},{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232-B24"}],"publication":"Genes","day":"30","year":"2021","isi":1,"has_accepted_license":"1","date_created":"2021-11-14T23:01:24Z","doi":"10.3390/genes12111746","date_published":"2021-10-30T00:00:00Z","acknowledgement":"This review was funded by the IMI2 Initiative under the grant AIMS-2-TRIALS No 777394, by the Hessian Ministry for Science and Arts; State of Hesse Ministry for Science and Arts: LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811); Research (BMBF) under the grant RAISE-genic No 779282 all to AGC. This work was also supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM) and by the Austrian Science Fund (FWF) (DK W1232-B24) both to G.N. and both BMBF GeNeRARe 01GM1519A and CRC 1080, project B10, of the German Research Foundation (DFG) to M.J.S, respectively. We want to thank R. Waltes for her support in preparing this manuscript.","oa":1,"publisher":"MDPI","quality_controlled":"1"},{"article_number":"e71575","title":"Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly","article_processing_charge":"No","external_id":{"isi":["000720945900001"]},"author":[{"last_name":"Conde-Dusman","full_name":"Conde-Dusman, María J","first_name":"María J"},{"first_name":"Partha N","last_name":"Dey","full_name":"Dey, Partha N"},{"full_name":"Elía-Zudaire, Óscar","last_name":"Elía-Zudaire","first_name":"Óscar"},{"first_name":"Luis E","id":"33D1B084-F248-11E8-B48F-1D18A9856A87","full_name":"Garcia Rabaneda, Luis E","last_name":"Garcia Rabaneda"},{"full_name":"García-Lira, Carmen","last_name":"García-Lira","first_name":"Carmen"},{"first_name":"Teddy","last_name":"Grand","full_name":"Grand, Teddy"},{"last_name":"Briz","full_name":"Briz, Victor","first_name":"Victor"},{"full_name":"Velasco, Eric R","last_name":"Velasco","first_name":"Eric R"},{"last_name":"Andero Galí","full_name":"Andero Galí, Raül","first_name":"Raül"},{"full_name":"Niñerola, Sergio","last_name":"Niñerola","first_name":"Sergio"},{"first_name":"Angel","last_name":"Barco","full_name":"Barco, Angel"},{"first_name":"Pierre","last_name":"Paoletti","full_name":"Paoletti, Pierre"},{"first_name":"John F","full_name":"Wesseling, John F","last_name":"Wesseling"},{"last_name":"Gardoni","full_name":"Gardoni, Fabrizio","first_name":"Fabrizio"},{"first_name":"Steven J","last_name":"Tavalin","full_name":"Tavalin, Steven J"},{"first_name":"Isabel","full_name":"Perez-Otaño, Isabel","last_name":"Perez-Otaño"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"mla":"Conde-Dusman, María J., et al. “Control of Protein Synthesis and Memory by GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1 Assembly.” ELife, vol. 10, e71575, eLife Sciences Publications, 2021, doi:10.7554/elife.71575.","apa":"Conde-Dusman, M. J., Dey, P. N., Elía-Zudaire, Ó., Garcia Rabaneda, L. E., García-Lira, C., Grand, T., … Perez-Otaño, I. (2021). Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.71575","ama":"Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, et al. Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife. 2021;10. doi:10.7554/elife.71575","ieee":"M. J. Conde-Dusman et al., “Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly,” eLife, vol. 10. eLife Sciences Publications, 2021.","short":"M.J. Conde-Dusman, P.N. Dey, Ó. Elía-Zudaire, L.E. Garcia Rabaneda, C. García-Lira, T. Grand, V. Briz, E.R. Velasco, R. Andero Galí, S. Niñerola, A. Barco, P. Paoletti, J.F. Wesseling, F. Gardoni, S.J. Tavalin, I. Perez-Otaño, ELife 10 (2021).","chicago":"Conde-Dusman, María J, Partha N Dey, Óscar Elía-Zudaire, Luis E Garcia Rabaneda, Carmen García-Lira, Teddy Grand, Victor Briz, et al. “Control of Protein Synthesis and Memory by GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1 Assembly.” ELife. eLife Sciences Publications, 2021. https://doi.org/10.7554/elife.71575.","ista":"Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, Garcia Rabaneda LE, García-Lira C, Grand T, Briz V, Velasco ER, Andero Galí R, Niñerola S, Barco A, Paoletti P, Wesseling JF, Gardoni F, Tavalin SJ, Perez-Otaño I. 2021. Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife. 10, e71575."},"oa":1,"quality_controlled":"1","publisher":"eLife Sciences Publications","acknowledgement":"We thank Stuart Lipton and Nobuki Nakanishi for providing the Grin3a knockout mice, Beverly Davidson for the AAV-caRheb, Jose Esteban for help with behavioral and biochemical experiments, and Noelia Campillo, Rebeca Martínez-Turrillas, and Ana Navarro for expert technical help. Work was funded by the UTE project CIMA; fellowships from the Fundación Tatiana Pérez de Guzmán el Bueno, FEBS, and IBRO (to M.J.C.D.), Generalitat Valenciana (to O.E.-Z.), Juan de la Cierva (to L.G.R.), FPI-MINECO (to E.R.V., to S.N.) and Intertalentum postdoctoral program (to V.B.); ANR (GluBrain3A) and ERC Advanced Grants (#693021) (to P.P.); Ramón y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R, ERANET-Neuron JTC 2019 ISCIII AC19/00077 FEDER funds (to R.A.); RETOS-MINECO SAF2017-87928-R (to A.B.); an NIH grant (NS76637) and UTHSC College of Medicine funds (to S.J.T.); and NARSAD Independent Investigator Award and grants from the MINECO (CSD2008-00005, SAF2013-48983R, SAF2016-80895-R), Generalitat Valenciana (PROMETEO 2019/020)(to I.P.O.) and Severo-Ochoa Excellence Awards (SEV-2013-0317, SEV-2017-0723).","date_created":"2021-11-18T06:59:45Z","date_published":"2021-11-17T00:00:00Z","doi":"10.7554/elife.71575","publication":"eLife","day":"17","year":"2021","isi":1,"has_accepted_license":"1","keyword":["general immunology and microbiology","general biochemistry","genetics and molecular biology","general medicine","general neuroscience"],"status":"public","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_type":"original","type":"journal_article","_id":"10301","department":[{"_id":"GaNo"}],"file_date_updated":"2021-11-18T07:02:02Z","ddc":["570"],"date_updated":"2023-08-14T11:50:50Z","intvolume":" 10","month":"11","oa_version":"Published Version","abstract":[{"text":"De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.","lang":"eng"}],"volume":10,"language":[{"iso":"eng"}],"file":[{"file_name":"elife-71575-v1.pdf","date_created":"2021-11-18T07:02:02Z","creator":"lgarciar","file_size":2477302,"date_updated":"2021-11-18T07:02:02Z","success":1,"checksum":"59318e9e41507cec83c2f4070e6ad540","file_id":"10302","relation":"main_file","access_level":"open_access","content_type":"application/pdf"}],"publication_status":"published","publication_identifier":{"issn":["2050-084X"]}},{"acknowledgement":"We acknowledge that Université Laval stands on the traditional and unceded land of the Huron-Wendat peoples; and that the University of Victoria exists on the territory of the Lekwungen peoples and that the Songhees, Esquimalt and WSÁNEÆ peoples have relationships to this land. We thank Emmanuel Planel for the access to the epifluorescence microscope and Julie-Christine Lévesque at the Bioimaging Platform of CRCHU de Québec-Université Laval for technical assistance. We also thank the Centre for Advanced Materials and Related Technology for the access to the confocal microscope with Airyscan. K.P. was supported by a doctoral scholarship from Fonds de Recherche du Québec – Santé (FRQS), an excellence award from Fondation du CHU de Québec, as well as from Centre Thématique de Recherche en Neurosciences and from Fondation Famille-Choquette. K.B. was supported by excellence scholarships from Université Laval and Fondation du CHU de Québec. S.G. is supported by FIRC-AIRC fellowship for Italy 22329/2018 and by Pilot ARISLA NKINALS 2019. C.W.H. and J.C.S. were supported by postdoctoral fellowships from FRQS. This study was funded by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant (RGPIN-2014-05308) awarded to M.E.T., by ERANET neuron 2017 MicroSynDep to M.E.T. and I.B., and by the Italian Ministry of Health, grant RF-2018-12367249 to I.B, by PRIN 2017, AIRC 2019 and Ministero della Salute RF2018 to C.L. M.E.T. is a Tier II Canada Research Chair in Neurobiology of Aging and Cognition.","quality_controlled":"1","publisher":"Elsevier","oa":1,"isi":1,"year":"2021","day":"01","publication":"Brain, Behavior, and Immunity","page":"423-439","doi":"10.1016/j.bbi.2021.07.022","date_published":"2021-10-01T00:00:00Z","date_created":"2021-08-22T22:01:21Z","citation":{"ista":"Picard K, Bisht K, Poggini S, Garofalo S, Golia MT, Basilico B, Abdallah F, Ciano Albanese N, Amrein I, Vernoux N, Sharma K, Hui CW, C. Savage J, Limatola C, Ragozzino D, Maggi L, Branchi I, Tremblay MÈ. 2021. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. 97, 423–439.","chicago":"Picard, Katherine, Kanchan Bisht, Silvia Poggini, Stefano Garofalo, Maria Teresa Golia, Bernadette Basilico, Fatima Abdallah, et al. “Microglial-Glucocorticoid Receptor Depletion Alters the Response of Hippocampal Microglia and Neurons in a Chronic Unpredictable Mild Stress Paradigm in Female Mice.” Brain, Behavior, and Immunity. Elsevier, 2021. https://doi.org/10.1016/j.bbi.2021.07.022.","short":"K. Picard, K. Bisht, S. Poggini, S. Garofalo, M.T. Golia, B. Basilico, F. Abdallah, N. Ciano Albanese, I. Amrein, N. Vernoux, K. Sharma, C.W. Hui, J. C. Savage, C. Limatola, D. Ragozzino, L. Maggi, I. Branchi, M.È. Tremblay, Brain, Behavior, and Immunity 97 (2021) 423–439.","ieee":"K. Picard et al., “Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice,” Brain, Behavior, and Immunity, vol. 97. Elsevier, pp. 423–439, 2021.","ama":"Picard K, Bisht K, Poggini S, et al. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. 2021;97:423-439. doi:10.1016/j.bbi.2021.07.022","apa":"Picard, K., Bisht, K., Poggini, S., Garofalo, S., Golia, M. T., Basilico, B., … Tremblay, M. È. (2021). Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. Elsevier. https://doi.org/10.1016/j.bbi.2021.07.022","mla":"Picard, Katherine, et al. “Microglial-Glucocorticoid Receptor Depletion Alters the Response of Hippocampal Microglia and Neurons in a Chronic Unpredictable Mild Stress Paradigm in Female Mice.” Brain, Behavior, and Immunity, vol. 97, Elsevier, 2021, pp. 423–39, doi:10.1016/j.bbi.2021.07.022."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","author":[{"last_name":"Picard","full_name":"Picard, Katherine","first_name":"Katherine"},{"last_name":"Bisht","full_name":"Bisht, Kanchan","first_name":"Kanchan"},{"full_name":"Poggini, Silvia","last_name":"Poggini","first_name":"Silvia"},{"first_name":"Stefano","last_name":"Garofalo","full_name":"Garofalo, Stefano"},{"first_name":"Maria Teresa","last_name":"Golia","full_name":"Golia, Maria Teresa"},{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","last_name":"Basilico","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette"},{"first_name":"Fatima","full_name":"Abdallah, Fatima","last_name":"Abdallah"},{"first_name":"Naomi","last_name":"Ciano Albanese","full_name":"Ciano Albanese, Naomi"},{"first_name":"Irmgard","last_name":"Amrein","full_name":"Amrein, Irmgard"},{"last_name":"Vernoux","full_name":"Vernoux, Nathalie","first_name":"Nathalie"},{"full_name":"Sharma, Kaushik","last_name":"Sharma","first_name":"Kaushik"},{"last_name":"Hui","full_name":"Hui, Chin Wai","first_name":"Chin Wai"},{"last_name":"C. Savage","full_name":"C. Savage, Julie","first_name":"Julie"},{"last_name":"Limatola","full_name":"Limatola, Cristina","first_name":"Cristina"},{"last_name":"Ragozzino","full_name":"Ragozzino, Davide","first_name":"Davide"},{"last_name":"Maggi","full_name":"Maggi, Laura","first_name":"Laura"},{"first_name":"Igor","full_name":"Branchi, Igor","last_name":"Branchi"},{"last_name":"Tremblay","full_name":"Tremblay, Marie Ève","first_name":"Marie Ève"}],"external_id":{"pmid":["34343616"],"isi":["000702878400007"]},"article_processing_charge":"No","title":"Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice","abstract":[{"lang":"eng","text":"Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal’s ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress."}],"pmid":1,"oa_version":"Submitted Version","scopus_import":"1","main_file_link":[{"open_access":"1","url":"https://www.zora.uzh.ch/id/eprint/208855/1/ZORA208855.pdf"}],"month":"10","intvolume":" 97","publication_identifier":{"issn":["0889-1591"]},"publication_status":"published","language":[{"iso":"eng"}],"volume":97,"_id":"9953","type":"journal_article","article_type":"original","status":"public","date_updated":"2023-10-03T09:49:18Z","department":[{"_id":"GaNo"}]},{"volume":41,"issue":"7","publication_identifier":{"issn":["0271-678x"],"eissn":["1559-7016"]},"publication_status":"published","language":[{"iso":"eng"}],"scopus_import":"1","main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221757/"}],"month":"07","intvolume":" 41","abstract":[{"text":"P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood–brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3). Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced VT,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.","lang":"eng"}],"pmid":1,"oa_version":"Published Version","department":[{"_id":"GaNo"}],"date_updated":"2023-10-18T06:45:30Z","type":"journal_article","article_type":"original","status":"public","_id":"8730","page":"1634-1646","doi":"10.1177/0271678X20965500","date_published":"2021-07-01T00:00:00Z","date_created":"2020-11-06T08:39:01Z","isi":1,"year":"2021","day":"01","publication":"Journal of Cerebral Blood Flow and Metabolism","quality_controlled":"1","publisher":"SAGE Publications","oa":1,"author":[{"last_name":"Tournier","full_name":"Tournier, N","first_name":"N"},{"first_name":"S","full_name":"Goutal, S","last_name":"Goutal"},{"first_name":"S","last_name":"Mairinger","full_name":"Mairinger, S"},{"full_name":"Lozano, IH","last_name":"Lozano","first_name":"IH"},{"full_name":"Filip, T","last_name":"Filip","first_name":"T"},{"last_name":"Sauberer","full_name":"Sauberer, M","first_name":"M"},{"first_name":"F","full_name":"Caillé, F","last_name":"Caillé"},{"first_name":"L","last_name":"Breuil","full_name":"Breuil, L"},{"full_name":"Stanek, J","last_name":"Stanek","first_name":"J"},{"last_name":"Freeman","full_name":"Freeman, AF","first_name":"AF"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"},{"full_name":"Truillet, C","last_name":"Truillet","first_name":"C"},{"last_name":"Wanek","full_name":"Wanek, T","first_name":"T"},{"full_name":"Langer, O","last_name":"Langer","first_name":"O"}],"article_processing_charge":"No","external_id":{"isi":["000664214100012"],"pmid":["33081568"]},"title":"Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib","citation":{"mla":"Tournier, N., et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain Barrier by Co-Infusion of Erlotinib and Tariquidar to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Journal of Cerebral Blood Flow and Metabolism, vol. 41, no. 7, SAGE Publications, 2021, pp. 1634–46, doi:10.1177/0271678X20965500.","short":"N. Tournier, S. Goutal, S. Mairinger, I. Lozano, T. Filip, M. Sauberer, F. Caillé, L. Breuil, J. Stanek, A. Freeman, G. Novarino, C. Truillet, T. Wanek, O. Langer, Journal of Cerebral Blood Flow and Metabolism 41 (2021) 1634–1646.","ieee":"N. Tournier et al., “Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib,” Journal of Cerebral Blood Flow and Metabolism, vol. 41, no. 7. SAGE Publications, pp. 1634–1646, 2021.","ama":"Tournier N, Goutal S, Mairinger S, et al. Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. 2021;41(7):1634-1646. doi:10.1177/0271678X20965500","apa":"Tournier, N., Goutal, S., Mairinger, S., Lozano, I., Filip, T., Sauberer, M., … Langer, O. (2021). Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. SAGE Publications. https://doi.org/10.1177/0271678X20965500","chicago":"Tournier, N, S Goutal, S Mairinger, IH Lozano, T Filip, M Sauberer, F Caillé, et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain Barrier by Co-Infusion of Erlotinib and Tariquidar to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Journal of Cerebral Blood Flow and Metabolism. SAGE Publications, 2021. https://doi.org/10.1177/0271678X20965500.","ista":"Tournier N, Goutal S, Mairinger S, Lozano I, Filip T, Sauberer M, Caillé F, Breuil L, Stanek J, Freeman A, Novarino G, Truillet C, Wanek T, Langer O. 2021. Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. 41(7), 1634–1646."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87"},{"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","author":[{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"id":"29A8453C-F248-11E8-B48F-1D18A9856A87","first_name":"Lena A","full_name":"Schwarz, Lena A","last_name":"Schwarz"},{"full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette"},{"orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","last_name":"Tasciyan","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren"},{"id":"38C393BE-F248-11E8-B48F-1D18A9856A87","first_name":"Georgi A","full_name":"Dimchev, Georgi A","orcid":"0000-0001-8370-6161","last_name":"Dimchev"},{"full_name":"Nicolas, Armel","last_name":"Nicolas","id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel"},{"full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline","last_name":"Kreuzinger","full_name":"Kreuzinger, Caroline"},{"last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph"},{"first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa","last_name":"Knaus"},{"last_name":"Dobler","full_name":"Dobler, Zoe","first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"full_name":"Cacci, Emanuele","last_name":"Cacci","first_name":"Emanuele"},{"last_name":"Schur","orcid":"0000-0003-4790-8078","full_name":"Schur, Florian KM","first_name":"Florian KM","id":"48AD8942-F248-11E8-B48F-1D18A9856A87"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","last_name":"Danzl","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"}],"external_id":{"isi":["000658769900010"]},"article_processing_charge":"No","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-23123-x","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021).","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x.","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058."},"project":[{"grant_number":"754411","name":"ISTplus - Postdoctoral Fellowships","_id":"260C2330-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","name":"Neural stem cells in autism and epilepsy","grant_number":"F07807"},{"_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Optical control of synaptic function via adhesion molecules","grant_number":"I03600"}],"article_number":"3058","doi":"10.1038/s41467-021-23123-x","date_published":"2021-05-24T00:00:00Z","date_created":"2021-05-28T11:49:46Z","day":"24","publication":"Nature Communications","isi":1,"has_accepted_license":"1","year":"2021","publisher":"Springer Nature","quality_controlled":"1","oa":1,"acknowledgement":"We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A. Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the management of our animal colony, as well as M. Schunn and the Preclinical Facility team for technical assistance. We thank K. Heesom and her team at the University of Bristol Proteomics Facility for the proteomics sample preparation, data generation, and analysis support. We thank Y. B. Simon for kindly providing the plasmid for lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration and the fruitful discussions. This work was supported by the ISTPlus postdoctoral fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D (I3600-B27).","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"file_date_updated":"2021-05-28T12:39:43Z","ddc":["572"],"date_updated":"2024-03-27T23:30:23Z","status":"public","keyword":["General Biochemistry","Genetics and Molecular Biology"],"type":"journal_article","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"_id":"9429","related_material":{"record":[{"id":"7800","status":"public","relation":"earlier_version"},{"status":"public","id":"12401","relation":"dissertation_contains"}],"link":[{"url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/","relation":"press_release"}]},"volume":12,"issue":"1","ec_funded":1,"file":[{"date_created":"2021-05-28T12:39:43Z","file_name":"2021_NatureCommunications_Morandell.pdf","date_updated":"2021-05-28T12:39:43Z","file_size":9358599,"creator":"kschuh","checksum":"337e0f7959c35ec959984cacdcb472ba","file_id":"9430","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file"}],"language":[{"iso":"eng"}],"publication_identifier":{"eissn":["2041-1723"]},"publication_status":"published","month":"05","intvolume":" 12","oa_version":"Published Version","acknowledged_ssus":[{"_id":"PreCl"}],"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.","lang":"eng"}]},{"acknowledgement":" Dipartimento DiSS, Università degli Studi di Milano, Grant/Award Number: Linea 2; Fondazione Cariplo, Grant/Award Number: 2015-0783; German Federal Ministry of Education and Research (BMBF), Grant/Award Number: CHROMATIN-Net; Medical Faculty of the University of Lübeck, Grant/Award Number: J09-2017; Nickel & Co S.p.A.; Università degli Studi di Milano, Grant/Award Numbers: Molecular & Translational Medicine PhD Scholarship, Translational Medicine PhD Scholarship","quality_controlled":"1","publisher":"Wiley","year":"2020","isi":1,"publication":"Clinical Genetics","day":"01","page":"3-11","date_created":"2019-12-04T16:10:59Z","date_published":"2020-01-01T00:00:00Z","doi":"10.1111/cge.13674","citation":{"mla":"Avagliano, Laura, et al. “Chromatinopathies: A Focus on Cornelia de Lange Syndrome.” Clinical Genetics, vol. 97, no. 1, Wiley, 2020, pp. 3–11, doi:10.1111/cge.13674.","short":"L. Avagliano, I. Parenti, P. Grazioli, E. Di Fede, C. Parodi, M. Mariani, F.J. Kaiser, A. Selicorni, C. Gervasini, V. Massa, Clinical Genetics 97 (2020) 3–11.","ieee":"L. Avagliano et al., “Chromatinopathies: A focus on Cornelia de Lange syndrome,” Clinical Genetics, vol. 97, no. 1. Wiley, pp. 3–11, 2020.","apa":"Avagliano, L., Parenti, I., Grazioli, P., Di Fede, E., Parodi, C., Mariani, M., … Massa, V. (2020). Chromatinopathies: A focus on Cornelia de Lange syndrome. Clinical Genetics. Wiley. https://doi.org/10.1111/cge.13674","ama":"Avagliano L, Parenti I, Grazioli P, et al. Chromatinopathies: A focus on Cornelia de Lange syndrome. Clinical Genetics. 2020;97(1):3-11. doi:10.1111/cge.13674","chicago":"Avagliano, Laura, Ilaria Parenti, Paolo Grazioli, Elisabetta Di Fede, Chiara Parodi, Milena Mariani, Frank J. Kaiser, Angelo Selicorni, Cristina Gervasini, and Valentina Massa. “Chromatinopathies: A Focus on Cornelia de Lange Syndrome.” Clinical Genetics. Wiley, 2020. https://doi.org/10.1111/cge.13674.","ista":"Avagliano L, Parenti I, Grazioli P, Di Fede E, Parodi C, Mariani M, Kaiser FJ, Selicorni A, Gervasini C, Massa V. 2020. Chromatinopathies: A focus on Cornelia de Lange syndrome. Clinical Genetics. 97(1), 3–11."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_processing_charge":"No","external_id":{"pmid":["31721174"],"isi":["000562561800001"]},"author":[{"last_name":"Avagliano","full_name":"Avagliano, Laura","first_name":"Laura"},{"id":"D93538B0-5B71-11E9-AC62-02EBE5697425","first_name":"Ilaria","last_name":"Parenti","full_name":"Parenti, Ilaria"},{"first_name":"Paolo","last_name":"Grazioli","full_name":"Grazioli, Paolo"},{"full_name":"Di Fede, Elisabetta","last_name":"Di Fede","first_name":"Elisabetta"},{"full_name":"Parodi, Chiara","last_name":"Parodi","first_name":"Chiara"},{"first_name":"Milena","last_name":"Mariani","full_name":"Mariani, Milena"},{"first_name":"Frank J.","full_name":"Kaiser, Frank J.","last_name":"Kaiser"},{"first_name":"Angelo","last_name":"Selicorni","full_name":"Selicorni, Angelo"},{"first_name":"Cristina","last_name":"Gervasini","full_name":"Gervasini, Cristina"},{"first_name":"Valentina","full_name":"Massa, Valentina","last_name":"Massa"}],"title":"Chromatinopathies: A focus on Cornelia de Lange syndrome","abstract":[{"lang":"eng","text":"In recent years, many genes have been associated with chromatinopathies classified as “Cornelia de Lange Syndrome‐like.” It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that “CdLS‐like syndromes” are part of a larger “rare disease family” sharing multiple clinical features and common disrupted molecular pathways."}],"pmid":1,"oa_version":"None","scopus_import":"1","intvolume":" 97","month":"01","publication_status":"published","publication_identifier":{"eissn":["1399-0004"],"issn":["0009-9163"]},"language":[{"iso":"eng"}],"issue":"1","volume":97,"_id":"7149","article_type":"review","type":"journal_article","status":"public","date_updated":"2023-08-17T14:06:20Z","department":[{"_id":"GaNo"}]},{"oa":1,"quality_controlled":"1","publisher":"MDPI","date_created":"2020-02-16T23:00:49Z","doi":"10.3390/ijms21031042","date_published":"2020-02-04T00:00:00Z","year":"2020","has_accepted_license":"1","isi":1,"publication":"International Journal of Molecular Sciences","day":"04","article_number":"1042","external_id":{"isi":["000522551606028"]},"article_processing_charge":"No","author":[{"first_name":"Ana","last_name":"Latorre-Pellicer","full_name":"Latorre-Pellicer, Ana"},{"full_name":"Ascaso, Ángela","last_name":"Ascaso","first_name":"Ángela"},{"full_name":"Trujillano, Laura","last_name":"Trujillano","first_name":"Laura"},{"full_name":"Gil-Salvador, Marta","last_name":"Gil-Salvador","first_name":"Marta"},{"first_name":"Maria","last_name":"Arnedo","full_name":"Arnedo, Maria"},{"last_name":"Lucia-Campos","full_name":"Lucia-Campos, Cristina","first_name":"Cristina"},{"last_name":"Antoñanzas-Pérez","full_name":"Antoñanzas-Pérez, Rebeca","first_name":"Rebeca"},{"first_name":"Iñigo","last_name":"Marcos-Alcalde","full_name":"Marcos-Alcalde, Iñigo"},{"full_name":"Parenti, Ilaria","last_name":"Parenti","first_name":"Ilaria","id":"D93538B0-5B71-11E9-AC62-02EBE5697425"},{"full_name":"Bueno-Lozano, Gloria","last_name":"Bueno-Lozano","first_name":"Gloria"},{"first_name":"Antonio","last_name":"Musio","full_name":"Musio, Antonio"},{"full_name":"Puisac, Beatriz","last_name":"Puisac","first_name":"Beatriz"},{"first_name":"Frank J.","last_name":"Kaiser","full_name":"Kaiser, Frank J."},{"last_name":"Ramos","full_name":"Ramos, Feliciano J.","first_name":"Feliciano J."},{"first_name":"Paulino","last_name":"Gómez-Puertas","full_name":"Gómez-Puertas, Paulino"},{"first_name":"Juan","last_name":"Pié","full_name":"Pié, Juan"}],"title":"Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes","citation":{"chicago":"Latorre-Pellicer, Ana, Ángela Ascaso, Laura Trujillano, Marta Gil-Salvador, Maria Arnedo, Cristina Lucia-Campos, Rebeca Antoñanzas-Pérez, et al. “Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes.” International Journal of Molecular Sciences. MDPI, 2020. https://doi.org/10.3390/ijms21031042.","ista":"Latorre-Pellicer A, Ascaso Á, Trujillano L, Gil-Salvador M, Arnedo M, Lucia-Campos C, Antoñanzas-Pérez R, Marcos-Alcalde I, Parenti I, Bueno-Lozano G, Musio A, Puisac B, Kaiser FJ, Ramos FJ, Gómez-Puertas P, Pié J. 2020. Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes. International Journal of Molecular Sciences. 21(3), 1042.","mla":"Latorre-Pellicer, Ana, et al. “Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes.” International Journal of Molecular Sciences, vol. 21, no. 3, 1042, MDPI, 2020, doi:10.3390/ijms21031042.","ama":"Latorre-Pellicer A, Ascaso Á, Trujillano L, et al. Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes. International Journal of Molecular Sciences. 2020;21(3). doi:10.3390/ijms21031042","apa":"Latorre-Pellicer, A., Ascaso, Á., Trujillano, L., Gil-Salvador, M., Arnedo, M., Lucia-Campos, C., … Pié, J. (2020). Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes. International Journal of Molecular Sciences. MDPI. https://doi.org/10.3390/ijms21031042","short":"A. Latorre-Pellicer, Á. Ascaso, L. Trujillano, M. Gil-Salvador, M. Arnedo, C. Lucia-Campos, R. Antoñanzas-Pérez, I. Marcos-Alcalde, I. Parenti, G. Bueno-Lozano, A. Musio, B. Puisac, F.J. Kaiser, F.J. Ramos, P. Gómez-Puertas, J. Pié, International Journal of Molecular Sciences 21 (2020).","ieee":"A. Latorre-Pellicer et al., “Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes,” International Journal of Molecular Sciences, vol. 21, no. 3. MDPI, 2020."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","scopus_import":"1","intvolume":" 21","month":"02","abstract":[{"text":"Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.","lang":"eng"}],"oa_version":"Published Version","volume":21,"issue":"3","publication_status":"published","publication_identifier":{"issn":["16616596"],"eissn":["14220067"]},"language":[{"iso":"eng"}],"file":[{"content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_id":"7496","checksum":"0e6658c4fe329d55d4d9bef01c5b15d0","file_size":4271234,"date_updated":"2020-07-14T12:47:59Z","creator":"dernst","file_name":"2020_IntMolecSciences_Latorre.pdf","date_created":"2020-02-18T07:49:22Z"}],"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","status":"public","_id":"7488","department":[{"_id":"GaNo"}],"file_date_updated":"2020-07-14T12:47:59Z","date_updated":"2023-08-18T06:35:41Z","ddc":["570"]},{"article_number":"e103358","citation":{"mla":"Weinert, Stefanie, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange Causes Severe Neurodegeneration.” EMBO Journal, vol. 39, e103358, EMBO Press, 2020, doi:10.15252/embj.2019103358.","apa":"Weinert, S., Gimber, N., Deuschel, D., Stuhlmann, T., Puchkov, D., Farsi, Z., … Jentsch, T. J. (2020). Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal. EMBO Press. https://doi.org/10.15252/embj.2019103358","ama":"Weinert S, Gimber N, Deuschel D, et al. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal. 2020;39. doi:10.15252/embj.2019103358","short":"S. Weinert, N. Gimber, D. Deuschel, T. Stuhlmann, D. Puchkov, Z. Farsi, C.F. Ludwig, G. Novarino, K.I. López-Cayuqueo, R. Planells-Cases, T.J. Jentsch, EMBO Journal 39 (2020).","ieee":"S. Weinert et al., “Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration,” EMBO Journal, vol. 39. EMBO Press, 2020.","chicago":"Weinert, Stefanie, Niclas Gimber, Dorothea Deuschel, Till Stuhlmann, Dmytro Puchkov, Zohreh Farsi, Carmen F. Ludwig, et al. “Uncoupling Endosomal CLC Chloride/Proton Exchange Causes Severe Neurodegeneration.” EMBO Journal. EMBO Press, 2020. https://doi.org/10.15252/embj.2019103358.","ista":"Weinert S, Gimber N, Deuschel D, Stuhlmann T, Puchkov D, Farsi Z, Ludwig CF, Novarino G, López-Cayuqueo KI, Planells-Cases R, Jentsch TJ. 2020. Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration. EMBO Journal. 39, e103358."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","author":[{"first_name":"Stefanie","full_name":"Weinert, Stefanie","last_name":"Weinert"},{"last_name":"Gimber","full_name":"Gimber, Niclas","first_name":"Niclas"},{"full_name":"Deuschel, Dorothea","last_name":"Deuschel","first_name":"Dorothea"},{"first_name":"Till","last_name":"Stuhlmann","full_name":"Stuhlmann, Till"},{"last_name":"Puchkov","full_name":"Puchkov, Dmytro","first_name":"Dmytro"},{"last_name":"Farsi","full_name":"Farsi, Zohreh","first_name":"Zohreh"},{"full_name":"Ludwig, Carmen F.","last_name":"Ludwig","first_name":"Carmen F."},{"last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"},{"first_name":"Karen I.","full_name":"López-Cayuqueo, Karen I.","last_name":"López-Cayuqueo"},{"first_name":"Rosa","full_name":"Planells-Cases, Rosa","last_name":"Planells-Cases"},{"last_name":"Jentsch","full_name":"Jentsch, Thomas J.","first_name":"Thomas J."}],"external_id":{"pmid":["32118314"],"isi":["000517335000001"]},"article_processing_charge":"No","title":"Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration","acknowledgement":"We thank T. Stauber and T. Breiderhoff for cloning expression constructs; K. Räbel, S. Hohensee, and C. Backhaus for technical assistance; R. Jahn (MPIbpc, Göttingen) for providing the equipment required for SV purification; and A\r\nWoehler (MDC, Berlin) for assistance with SV imaging. Supported, in part, by grants from the Deutsche Forschungsgemeinschaft (JE164/9-2, SFB740 TP C5, FOR 2625 (JE164/14-1), NeuroCure Cluster of Excellence), the European Research Council Advanced Grant CYTOVOLION (ERC 294435) and the Prix Louis-Jeantet de Médecine to TJJ, and Peter and Traudl Engelhorn fellowship to ZF.","quality_controlled":"1","publisher":"EMBO Press","oa":1,"isi":1,"has_accepted_license":"1","year":"2020","day":"02","publication":"EMBO Journal","date_published":"2020-03-02T00:00:00Z","doi":"10.15252/embj.2019103358","date_created":"2020-03-15T23:00:55Z","_id":"7586","type":"journal_article","article_type":"original","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"status":"public","date_updated":"2023-08-18T07:07:36Z","ddc":["570"],"file_date_updated":"2020-07-14T12:48:00Z","department":[{"_id":"GaNo"}],"abstract":[{"lang":"eng","text":"CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl− concentration. Disruption of endosomal ClC‐3 causes severe neurodegeneration. To assess the importance of ClC‐3 Cl−/H+ exchange, we now generate Clcn3unc/unc mice in which ClC‐3 is converted into a Cl− channel. Unlike Clcn3−/− mice, Clcn3unc/unc mice appear normal owing to compensation by ClC‐4 with which ClC‐3 forms heteromers. ClC‐4 protein levels are strongly reduced in Clcn3−/−, but not in Clcn3unc/unc mice because ClC‐3unc binds and stabilizes ClC‐4 like wild‐type ClC‐3. Although mice lacking ClC‐4 appear healthy, its absence in Clcn3unc/unc/Clcn4−/− mice entails even stronger neurodegeneration than observed in Clcn3−/− mice. A fraction of ClC‐3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3unc/unc or Clcn3−/− mice before neurodegeneration sets in. Both, Cl−/H+‐exchange activity and the stabilizing effect on ClC‐4, are central to the biological function of ClC‐3."}],"oa_version":"Published Version","pmid":1,"scopus_import":"1","month":"03","intvolume":" 39","publication_identifier":{"issn":["02614189"],"eissn":["14602075"]},"publication_status":"published","file":[{"relation":"main_file","access_level":"open_access","content_type":"application/pdf","checksum":"82750a7a93e3740decbce8474004111a","file_id":"7615","creator":"dernst","file_size":12243278,"date_updated":"2020-07-14T12:48:00Z","file_name":"2020_EMBO_Weinert.pdf","date_created":"2020-03-23T13:51:11Z"}],"language":[{"iso":"eng"}],"volume":39,"license":"https://creativecommons.org/licenses/by-nc-nd/4.0/"},{"file_date_updated":"2020-07-14T12:48:04Z","department":[{"_id":"GaNo"}],"date_updated":"2023-08-21T06:27:47Z","ddc":["570"],"tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"type":"journal_article","article_type":"original","status":"public","_id":"7877","volume":31,"issue":"7","publication_status":"published","publication_identifier":{"eissn":["22111247"]},"language":[{"iso":"eng"}],"file":[{"date_created":"2020-05-26T11:05:01Z","file_name":"2020_CellReports_Parenti.pdf","date_updated":"2020-07-14T12:48:04Z","file_size":4695682,"creator":"dernst","checksum":"64d8f7467731ee5c166b10b939b8310b","file_id":"7892","content_type":"application/pdf","access_level":"open_access","relation":"main_file"}],"scopus_import":"1","intvolume":" 31","month":"05","abstract":[{"lang":"eng","text":"The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations inNIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus.Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions."}],"oa_version":"Published Version","article_processing_charge":"No","external_id":{"isi":["000535655200005"]},"author":[{"first_name":"Ilaria","id":"D93538B0-5B71-11E9-AC62-02EBE5697425","last_name":"Parenti","full_name":"Parenti, Ilaria"},{"first_name":"Farah","last_name":"Diab","full_name":"Diab, Farah"},{"first_name":"Sara Ruiz","full_name":"Gil, Sara Ruiz","last_name":"Gil"},{"full_name":"Mulugeta, Eskeatnaf","last_name":"Mulugeta","first_name":"Eskeatnaf"},{"full_name":"Casa, Valentina","last_name":"Casa","first_name":"Valentina"},{"first_name":"Riccardo","full_name":"Berutti, Riccardo","last_name":"Berutti"},{"first_name":"Rutger W.W.","last_name":"Brouwer","full_name":"Brouwer, Rutger W.W."},{"full_name":"Dupé, Valerie","last_name":"Dupé","first_name":"Valerie"},{"full_name":"Eckhold, Juliane","last_name":"Eckhold","first_name":"Juliane"},{"full_name":"Graf, Elisabeth","last_name":"Graf","first_name":"Elisabeth"},{"last_name":"Puisac","full_name":"Puisac, Beatriz","first_name":"Beatriz"},{"first_name":"Feliciano","full_name":"Ramos, Feliciano","last_name":"Ramos"},{"first_name":"Thomas","last_name":"Schwarzmayr","full_name":"Schwarzmayr, Thomas"},{"last_name":"Gines","full_name":"Gines, Macarena Moronta","first_name":"Macarena Moronta"},{"full_name":"Van Staveren, Thomas","last_name":"Van Staveren","first_name":"Thomas"},{"last_name":"Van Ijcken","full_name":"Van Ijcken, Wilfred F.J.","first_name":"Wilfred F.J."},{"full_name":"Strom, Tim M.","last_name":"Strom","first_name":"Tim M."},{"first_name":"Juan","full_name":"Pié, Juan","last_name":"Pié"},{"full_name":"Watrin, Erwan","last_name":"Watrin","first_name":"Erwan"},{"last_name":"Kaiser","full_name":"Kaiser, Frank J.","first_name":"Frank J."},{"full_name":"Wendt, Kerstin S.","last_name":"Wendt","first_name":"Kerstin S."}],"title":"MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome","citation":{"ista":"Parenti I, Diab F, Gil SR, Mulugeta E, Casa V, Berutti R, Brouwer RWW, Dupé V, Eckhold J, Graf E, Puisac B, Ramos F, Schwarzmayr T, Gines MM, Van Staveren T, Van Ijcken WFJ, Strom TM, Pié J, Watrin E, Kaiser FJ, Wendt KS. 2020. MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome. Cell Reports. 31(7), 107647.","chicago":"Parenti, Ilaria, Farah Diab, Sara Ruiz Gil, Eskeatnaf Mulugeta, Valentina Casa, Riccardo Berutti, Rutger W.W. Brouwer, et al. “MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.” Cell Reports. Elsevier, 2020. https://doi.org/10.1016/j.celrep.2020.107647.","ieee":"I. Parenti et al., “MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome,” Cell Reports, vol. 31, no. 7. Elsevier, 2020.","short":"I. Parenti, F. Diab, S.R. Gil, E. Mulugeta, V. Casa, R. Berutti, R.W.W. Brouwer, V. Dupé, J. Eckhold, E. Graf, B. Puisac, F. Ramos, T. Schwarzmayr, M.M. Gines, T. Van Staveren, W.F.J. Van Ijcken, T.M. Strom, J. Pié, E. Watrin, F.J. Kaiser, K.S. Wendt, Cell Reports 31 (2020).","apa":"Parenti, I., Diab, F., Gil, S. R., Mulugeta, E., Casa, V., Berutti, R., … Wendt, K. S. (2020). MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2020.107647","ama":"Parenti I, Diab F, Gil SR, et al. MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome. Cell Reports. 2020;31(7). doi:10.1016/j.celrep.2020.107647","mla":"Parenti, Ilaria, et al. “MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.” Cell Reports, vol. 31, no. 7, 107647, Elsevier, 2020, doi:10.1016/j.celrep.2020.107647."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_number":"107647","date_created":"2020-05-24T22:00:57Z","doi":"10.1016/j.celrep.2020.107647","date_published":"2020-05-19T00:00:00Z","year":"2020","has_accepted_license":"1","isi":1,"publication":"Cell Reports","day":"19","oa":1,"publisher":"Elsevier","quality_controlled":"1"},{"date_updated":"2023-08-21T08:25:31Z","ddc":["570"],"department":[{"_id":"GaNo"}],"file_date_updated":"2020-11-25T09:43:40Z","_id":"7957","article_type":"original","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"status":"public","publication_identifier":{"issn":["01662236"],"eissn":["1878108X"]},"publication_status":"published","file":[{"success":1,"checksum":"67db0251b1d415ae59005f876fcf9e34","file_id":"8805","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"2020_TrendsNeuroscience_Parenti.pdf","date_created":"2020-11-25T09:43:40Z","file_size":1439550,"date_updated":"2020-11-25T09:43:40Z","creator":"dernst"}],"language":[{"iso":"eng"}],"issue":"8","volume":43,"ec_funded":1,"abstract":[{"lang":"eng","text":"Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function and are characterized by wide genetic and clinical variability. In this review, we discuss the multiple factors that influence the clinical presentation of NDDs, with particular attention to gene vulnerability, mutational load, and the two-hit model. Despite the complex architecture of\r\nmutational events associated with NDDs, the various proteins involved appear to converge on common pathways, such as synaptic plasticity/function, chromatin remodelers and the mammalian target of rapamycin (mTOR) pathway. A thorough understanding of the mechanisms behind these pathways will hopefully lead to the identification of candidates that could be targeted for treatment approaches."}],"oa_version":"Published Version","pmid":1,"scopus_import":"1","month":"08","intvolume":" 43","citation":{"mla":"Parenti, Ilaria, et al. “Neurodevelopmental Disorders: From Genetics to Functional Pathways.” Trends in Neurosciences, vol. 43, no. 8, Elsevier, 2020, pp. 608–21, doi:10.1016/j.tins.2020.05.004.","apa":"Parenti, I., Garcia Rabaneda, L. E., Schön, H., & Novarino, G. (2020). Neurodevelopmental disorders: From genetics to functional pathways. Trends in Neurosciences. Elsevier. https://doi.org/10.1016/j.tins.2020.05.004","ama":"Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. Neurodevelopmental disorders: From genetics to functional pathways. Trends in Neurosciences. 2020;43(8):608-621. doi:10.1016/j.tins.2020.05.004","ieee":"I. Parenti, L. E. Garcia Rabaneda, H. Schön, and G. Novarino, “Neurodevelopmental disorders: From genetics to functional pathways,” Trends in Neurosciences, vol. 43, no. 8. Elsevier, pp. 608–621, 2020.","short":"I. Parenti, L.E. Garcia Rabaneda, H. Schön, G. Novarino, Trends in Neurosciences 43 (2020) 608–621.","chicago":"Parenti, Ilaria, Luis E Garcia Rabaneda, Hanna Schön, and Gaia Novarino. “Neurodevelopmental Disorders: From Genetics to Functional Pathways.” Trends in Neurosciences. Elsevier, 2020. https://doi.org/10.1016/j.tins.2020.05.004.","ista":"Parenti I, Garcia Rabaneda LE, Schön H, Novarino G. 2020. Neurodevelopmental disorders: From genetics to functional pathways. Trends in Neurosciences. 43(8), 608–621."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","author":[{"id":"D93538B0-5B71-11E9-AC62-02EBE5697425","first_name":"Ilaria","full_name":"Parenti, Ilaria","last_name":"Parenti"},{"full_name":"Garcia Rabaneda, Luis E","last_name":"Garcia Rabaneda","id":"33D1B084-F248-11E8-B48F-1D18A9856A87","first_name":"Luis E"},{"first_name":"Hanna","id":"C8E17EDC-D7AA-11E9-B7B7-45ECE5697425","last_name":"Schön","full_name":"Schön, Hanna"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino"}],"article_processing_charge":"No","external_id":{"isi":["000553090600008"],"pmid":["32507511"]},"title":"Neurodevelopmental disorders: From genetics to functional pathways","project":[{"call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"}],"isi":1,"has_accepted_license":"1","year":"2020","day":"01","publication":"Trends in Neurosciences","page":"608-621","date_published":"2020-08-01T00:00:00Z","doi":"10.1016/j.tins.2020.05.004","date_created":"2020-06-14T22:00:49Z","acknowledgement":"We wish to thank Jasmin Morandell for generously sharing Figure 2. This work was supported by the European Research Council Starting Grant (grant 715508 ) to G.N.","publisher":"Elsevier","quality_controlled":"1","oa":1},{"publisher":"Institute of Science and Technology Austria","oa":1,"acknowledgement":"I would like to especially thank Armel Nicolas from the Proteomics and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka, Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line maintenance and their great support.","page":"138","doi":"10.15479/AT:ISTA:8620","date_published":"2020-10-12T00:00:00Z","date_created":"2020-10-07T14:53:13Z","has_accepted_license":"1","year":"2020","day":"12","project":[{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","grant_number":"W1232-B24","name":"Molecular Drug Targets"},{"name":"Neural stem cells in autism and epilepsy","grant_number":"F07807","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"}],"author":[{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","last_name":"Morandell","full_name":"Morandell, Jasmin"}],"article_processing_charge":"No","title":"Illuminating the role of Cul3 in autism spectrum disorder pathogenesis","citation":{"ista":"Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria.","chicago":"Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8620.","ama":"Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. 2020. doi:10.15479/AT:ISTA:8620","apa":"Morandell, J. (2020). Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8620","short":"J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis, Institute of Science and Technology Austria, 2020.","ieee":"J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,” Institute of Science and Technology Austria, 2020.","mla":"Morandell, Jasmin. Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8620."},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","alternative_title":["ISTA Thesis"],"month":"10","abstract":[{"text":"The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive.\r\nDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages.","lang":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"oa_version":"Published Version","related_material":{"record":[{"id":"7800","status":"public","relation":"part_of_dissertation"},{"id":"8131","status":"public","relation":"part_of_dissertation"}]},"publication_identifier":{"issn":["2663-337X"]},"degree_awarded":"PhD","publication_status":"published","file":[{"date_created":"2020-10-07T14:41:49Z","file_name":"Jasmin_Morandell_Thesis-2020_final.pdf","date_updated":"2021-10-16T22:30:04Z","file_size":16155786,"creator":"jmorande","file_id":"8621","checksum":"7ee83e42de3e5ce2fedb44dff472f75f","embargo":"2021-10-15","content_type":"application/pdf","access_level":"open_access","relation":"main_file"},{"content_type":"application/x-zip-compressed","embargo_to":"open_access","access_level":"closed","relation":"source_file","checksum":"5e0464af453734210ce7aab7b4a92e3a","file_id":"8622","date_updated":"2021-10-16T22:30:04Z","file_size":24344152,"creator":"jmorande","date_created":"2020-10-07T14:45:07Z","file_name":"Jasmin_Morandell_Thesis-2020_final.zip"}],"language":[{"iso":"eng"}],"type":"dissertation","status":"public","_id":"8620","department":[{"_id":"GaNo"}],"file_date_updated":"2021-10-16T22:30:04Z","supervisor":[{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"date_updated":"2023-09-07T13:22:14Z","ddc":["610"]},{"_id":"7800","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"type":"preprint","status":"public","date_updated":"2024-03-27T23:30:14Z","ddc":["570"],"file_date_updated":"2020-07-14T12:48:03Z","department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.","lang":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"}],"oa_version":"Preprint","month":"01","publication_status":"submitted","language":[{"iso":"eng"}],"file":[{"file_id":"7801","checksum":"c6799ab5daba80efe8e2ed63c15f8c81","access_level":"open_access","relation":"main_file","content_type":"application/pdf","date_created":"2020-05-05T14:31:19Z","file_name":"2020.01.10.902064v1.full.pdf","creator":"rsix","date_updated":"2020-07-14T12:48:03Z","file_size":2931370}],"related_material":{"record":[{"status":"public","id":"9429","relation":"later_version"},{"status":"public","id":"8620","relation":"dissertation_contains"}]},"project":[{"call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","name":"Optical control of synaptic function via adhesion molecules","grant_number":"I03600"},{"name":"Molecular Drug Targets","grant_number":"W1232-B24","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"citation":{"chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 .","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, 10.1101/2020.01.10.902064 .","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 .","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. doi:10.1101/2020.01.10.902064 ","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064 ","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” bioRxiv. Cold Spring Harbor Laboratory.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.)."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","author":[{"last_name":"Morandell","full_name":"Morandell, Jasmin","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","last_name":"Schwarz","full_name":"Schwarz, Lena A"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico"},{"last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X","first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87"},{"id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","last_name":"Nicolas","full_name":"Nicolas, Armel"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87","full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger"},{"id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa","full_name":"Knaus, Lisa","last_name":"Knaus"},{"full_name":"Dobler, Zoe","last_name":"Dobler","id":"D23090A2-9057-11EA-883A-A8396FC7A38F","first_name":"Zoe"},{"last_name":"Cacci","full_name":"Cacci, Emanuele","first_name":"Emanuele"},{"first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","last_name":"Danzl"},{"orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","oa":1,"publisher":"Cold Spring Harbor Laboratory","year":"2020","has_accepted_license":"1","publication":"bioRxiv","day":"11","date_created":"2020-05-05T14:31:33Z","doi":"10.1101/2020.01.10.902064 ","date_published":"2020-01-11T00:00:00Z"},{"publisher":"Elsevier","quality_controlled":"1","oa":1,"doi":"10.1016/j.gde.2020.06.004","date_published":"2020-12-01T00:00:00Z","date_created":"2020-07-19T22:00:58Z","page":"126-137","day":"01","publication":"Current Opinion in Genetics and Development","has_accepted_license":"1","isi":1,"year":"2020","project":[{"grant_number":"754411","name":"ISTplus - Postdoctoral Fellowships","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425"},{"name":"Molecular Drug Targets","grant_number":"W1232-B24","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"},{"name":"Neural stem cells in autism and epilepsy","grant_number":"F07807","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"}],"title":"Molecular mechanisms for targeted ASD treatments","author":[{"orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino"}],"external_id":{"pmid":["32659636"],"isi":["000598918900019"]},"article_processing_charge":"Yes (via OA deal)","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"mla":"Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development, vol. 65, no. 12, Elsevier, 2020, pp. 126–37, doi:10.1016/j.gde.2020.06.004.","ieee":"B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted ASD treatments,” Current Opinion in Genetics and Development, vol. 65, no. 12. Elsevier, pp. 126–137, 2020.","short":"B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development 65 (2020) 126–137.","ama":"Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 2020;65(12):126-137. doi:10.1016/j.gde.2020.06.004","apa":"Basilico, B., Morandell, J., & Novarino, G. (2020). Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. Elsevier. https://doi.org/10.1016/j.gde.2020.06.004","chicago":"Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development. Elsevier, 2020. https://doi.org/10.1016/j.gde.2020.06.004.","ista":"Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137."},"month":"12","intvolume":" 65","scopus_import":"1","oa_version":"Published Version","pmid":1,"abstract":[{"lang":"eng","text":"The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes."}],"volume":65,"issue":"12","related_material":{"record":[{"relation":"dissertation_contains","id":"8620","status":"public"}]},"ec_funded":1,"file":[{"file_size":1381545,"date_updated":"2020-07-22T06:47:45Z","creator":"dernst","file_name":"2020_CurrentOpGenetics_Basilico.pdf","date_created":"2020-07-22T06:47:45Z","content_type":"application/pdf","relation":"main_file","access_level":"open_access","success":1,"file_id":"8146"}],"language":[{"iso":"eng"}],"publication_identifier":{"issn":["0959437X"],"eissn":["18790380"]},"publication_status":"published","status":"public","type":"journal_article","article_type":"original","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"_id":"8131","file_date_updated":"2020-07-22T06:47:45Z","department":[{"_id":"GaNo"}],"ddc":["570"],"date_updated":"2024-03-27T23:30:14Z"},{"date_updated":"2023-08-24T14:28:24Z","department":[{"_id":"GaNo"}],"_id":"105","status":"public","type":"journal_article","article_type":"original","language":[{"iso":"eng"}],"publication_status":"published","volume":27,"pmid":1,"oa_version":"Published Version","abstract":[{"text":"Clinical Utility Gene Card. 1. Name of Disease (Synonyms): Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# of the Disease: 615809 and 615686. 3. Name of the Analysed Genes or DNA/Chromosome Segments: AMPD2 at 1p13.3. 4. OMIM# of the Gene(s): 102771.","lang":"eng"}],"month":"01","intvolume":" 27","scopus_import":"1","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1038/s41431-018-0231-2"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"mla":"Marsh, Ashley, et al. “CUGC for Pontocerebellar Hypoplasia Type 9 and Spastic Paraplegia-63.” European Journal of Human Genetics, vol. 27, Springer Nature, 2019, pp. 161–66, doi:10.1038/s41431-018-0231-2.","ama":"Marsh A, Novarino G, Lockhart P, Leventer R. CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63. European Journal of Human Genetics. 2019;27:161-166. doi:10.1038/s41431-018-0231-2","apa":"Marsh, A., Novarino, G., Lockhart, P., & Leventer, R. (2019). CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63. European Journal of Human Genetics. Springer Nature. https://doi.org/10.1038/s41431-018-0231-2","short":"A. Marsh, G. Novarino, P. Lockhart, R. Leventer, European Journal of Human Genetics 27 (2019) 161–166.","ieee":"A. Marsh, G. Novarino, P. Lockhart, and R. Leventer, “CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63,” European Journal of Human Genetics, vol. 27. Springer Nature, pp. 161–166, 2019.","chicago":"Marsh, Ashley, Gaia Novarino, Paul Lockhart, and Richard Leventer. “CUGC for Pontocerebellar Hypoplasia Type 9 and Spastic Paraplegia-63.” European Journal of Human Genetics. Springer Nature, 2019. https://doi.org/10.1038/s41431-018-0231-2.","ista":"Marsh A, Novarino G, Lockhart P, Leventer R. 2019. CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63. European Journal of Human Genetics. 27, 161–166."},"title":"CUGC for pontocerebellar hypoplasia type 9 and spastic paraplegia-63","publist_id":"7949","author":[{"full_name":"Marsh, Ashley","last_name":"Marsh","first_name":"Ashley"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Paul","last_name":"Lockhart","full_name":"Lockhart, Paul"},{"first_name":"Richard","full_name":"Leventer, Richard","last_name":"Leventer"}],"external_id":{"pmid":["30089829"],"isi":["000454111500019"]},"article_processing_charge":"No","day":"01","publication":"European Journal of Human Genetics","isi":1,"year":"2019","doi":"10.1038/s41431-018-0231-2","date_published":"2019-01-01T00:00:00Z","date_created":"2018-12-11T11:44:39Z","page":"161-166","acknowledgement":"This work was supported by EuroGentest2 (Unit 2: “Genetic testing as part of health care”), a Coordination Action under FP7 (Grant Agreement Number 261469) and the European Society of Human Genetics. We acknowledge the participation of the patients and their families in these studies, as well as the generous financial support of the Lefroy and Handbury families. APLM was supported by an Australian Postgraduate Award. PJL is supported by an NHMRC Career Development Fellowship (GNT1032364). RJL is supported by a Melbourne Children’s Clinician Scientist Fellowship.","publisher":"Springer Nature","quality_controlled":"1","oa":1}]