--- _id: '13107' abstract: - lang: eng text: "Within the human body, the brain exhibits the highest rate of energy consumption amongst all organs, with the majority of generated ATP being utilized to sustain neuronal activity. Therefore, the metabolism of the mature cerebral cortex is geared towards preserving metabolic homeostasis whilst generating significant amounts of energy. This requires a precise interplay between diverse metabolic pathways, spanning from a tissue-wide scale to the level of individual neurons. Disturbances to this delicate metabolic equilibrium, such as those resulting from maternal malnutrition\r\nor mutations affecting metabolic enzymes, often result in neuropathological variants of neurodevelopment. For instance, mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), have been associated with autism and microcephaly. However, despite recent progress in the field, the extent of metabolic restructuring that occurs within the developing brain and the corresponding alterations in nutrient demands during various critical periods remain largely unknown. To investigate this, we performed metabolomic profiling of the murine cerebral cortex to characterize the metabolic state of the forebrain at different developmental stages. We found that the developing cortex undergoes substantial metabolic reprogramming, with specific sets of metabolites displaying stage-specific changes. According to our observations, we determined a distinct temporal period in postnatal development during which the cortex displays heightened reliance on LNAAs. Hence, using a conditional knock-out mouse model, we deleted Slc7a5 in neural cells, allowing us to monitor the impact of a perturbed neuronal metabolic state across multiple developmental stages of corticogenesis. We found that manipulating the levels of essential LNAAs in cortical neurons in vivo affects one particular perinatal developmental period critical for cortical network refinement. Abnormally low intracellular LNAA levels result in cell-autonomous alterations in neuronal lipid metabolism, excitability, and survival during this particular time window. Although most of the effects of Slc7a5 deletion on neuronal physiology are transient, derailment of these processes during this brief but crucial window leads to long-term circuit dysfunction in mice. In conclusion, out data indicate that the cerebral cortex undergoes significant metabolic reorganization during development. This process involves the intricate integration of multiple metabolic pathways to ensure optimal neuronal function throughout different developmental stages. Our findings offer a paradigm for understanding how neurons synchronize the expression of nutrient-related genes with their activity to allow proper brain maturation. Further, our results demonstrate that disruptions in these precisely calibrated metabolic processes during critical periods of brain development may result in neuropathological outcomes in mice and in humans." acknowledged_ssus: - _id: PreCl - _id: Bio - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus citation: ama: 'Knaus L. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. 2023. doi:10.15479/at:ista:13107' apa: 'Knaus, L. (2023). The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:13107' chicago: 'Knaus, Lisa. “The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival.” Institute of Science and Technology Austria, 2023. https://doi.org/10.15479/at:ista:13107.' ieee: 'L. Knaus, “The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival,” Institute of Science and Technology Austria, 2023.' ista: 'Knaus L. 2023. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. Institute of Science and Technology Austria.' mla: 'Knaus, Lisa. The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival. Institute of Science and Technology Austria, 2023, doi:10.15479/at:ista:13107.' short: 'L. Knaus, The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival, Institute of Science and Technology Austria, 2023.' date_created: 2023-06-01T09:05:24Z date_published: 2023-05-31T00:00:00Z date_updated: 2024-02-07T08:03:33Z day: '31' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: GaNo doi: 10.15479/at:ista:13107 ec_funded: 1 file: - access_level: closed checksum: 4b69a4ac0bbf4163d59c0b58dcb4f2c3 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: lknaus date_created: 2023-06-01T13:48:41Z date_updated: 2023-06-01T13:48:41Z file_id: '13112' file_name: Thesis_Lisa Knaus_approved_final.docx file_size: 12991551 relation: source_file - access_level: open_access checksum: 6903d152aa01181d87a696085af31c83 content_type: application/pdf creator: lknaus date_created: 2023-06-02T09:47:29Z date_updated: 2023-06-07T08:41:49Z file_id: '13114' file_name: Thesis_Lisa Knaus_approved_final_pdfa2b.pdf file_size: 9309015 relation: main_file file_date_updated: 2023-06-07T08:41:49Z has_accepted_license: '1' language: - iso: eng month: '05' oa: 1 oa_version: Published Version page: '147' project: - _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 - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets publication_identifier: issn: - 2663 - 337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '12802' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 title: 'The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival' type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2023' ... --- _id: '12802' abstract: - lang: eng text: Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction. acknowledged_ssus: - _id: PreCl - _id: EM-Fac - _id: Bio - _id: LifeSc acknowledgement: We thank A. Freeman and V. Voronin for technical assistance, S. Deixler, A. Stichelberger, M. Schunn, and the Preclinical Facility for managing our animal colony. We thank L. Andersen and J. Sonntag, who were involved in generating the MADM lines. We thank the ISTA LSF Mass Spectrometry Core Facility for assistance with the proteomic analysis, as well as the ISTA electron microscopy and Imaging and Optics facility for technical support. Metabolomics LC-MS/MS analysis was performed by the Metabolomics Facility at Vienna BioCenter Core Facilities (VBCF). We acknowledge the support of the EMBL Metabolomics Core Facility (MCF) for lipidomics and intracellular metabolomics mass spectrometry data acquisition and analysis. RNA sequencing was performed by the Next Generation Sequencing Facility at VBCF. Schematics were generated using Biorender.com. This work was supported by the Austrian Science Fund (FWF, DK W1232-B24) and by the European Union’s Horizon 2020 research and innovation program (ERC) grant 725780 (LinPro) to S.H. and 715508 (REVERSEAUTISM) to G.N. article_processing_charge: Yes (via OA deal) article_type: original author: - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Bernadette full_name: Basilico, Bernadette id: 36035796-5ACA-11E9-A75E-7AF2E5697425 last_name: Basilico orcid: 0000-0003-1843-3173 - first_name: Daniel full_name: Malzl, Daniel last_name: Malzl - first_name: Maria full_name: Gerykova Bujalkova, Maria last_name: Gerykova Bujalkova - first_name: Mateja full_name: Smogavec, Mateja last_name: Smogavec - first_name: Lena A. full_name: Schwarz, Lena A. last_name: Schwarz - first_name: Sarah full_name: Gorkiewicz, Sarah id: f141a35d-15a9-11ec-9fb2-fef6becc7b6f last_name: Gorkiewicz - first_name: Nicole full_name: Amberg, Nicole id: 4CD6AAC6-F248-11E8-B48F-1D18A9856A87 last_name: Amberg orcid: 0000-0002-3183-8207 - first_name: Florian full_name: Pauler, Florian id: 48EA0138-F248-11E8-B48F-1D18A9856A87 last_name: Pauler orcid: 0000-0002-7462-0048 - first_name: Christian full_name: Knittl-Frank, Christian last_name: Knittl-Frank - first_name: Marianna full_name: Tassinari, Marianna id: 7af593f1-d44a-11ed-bf94-a3646a6bb35e last_name: Tassinari - first_name: Nuno full_name: Maulide, Nuno last_name: Maulide - first_name: Thomas full_name: Rülicke, Thomas last_name: Rülicke - first_name: Jörg full_name: Menche, Jörg last_name: Menche - first_name: Simon full_name: Hippenmeyer, Simon id: 37B36620-F248-11E8-B48F-1D18A9856A87 last_name: Hippenmeyer orcid: 0000-0003-2279-1061 - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Knaus L, Basilico B, Malzl D, et al. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 2023;186(9):1950-1967.e25. doi:10.1016/j.cell.2023.02.037 apa: Knaus, L., Basilico, B., Malzl, D., Gerykova Bujalkova, M., Smogavec, M., Schwarz, L. A., … Novarino, G. (2023). Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. Elsevier. https://doi.org/10.1016/j.cell.2023.02.037 chicago: Knaus, Lisa, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A. Schwarz, Sarah Gorkiewicz, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell. Elsevier, 2023. https://doi.org/10.1016/j.cell.2023.02.037. ieee: L. Knaus et al., “Large neutral amino acid levels tune perinatal neuronal excitability and survival,” Cell, vol. 186, no. 9. Elsevier, p. 1950–1967.e25, 2023. ista: Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA, Gorkiewicz S, Amberg N, Pauler F, Knittl-Frank C, Tassinari M, Maulide N, Rülicke T, Menche J, Hippenmeyer S, Novarino G. 2023. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 186(9), 1950–1967.e25. mla: Knaus, Lisa, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell, vol. 186, no. 9, Elsevier, 2023, p. 1950–1967.e25, doi:10.1016/j.cell.2023.02.037. short: L. Knaus, B. Basilico, D. Malzl, M. Gerykova Bujalkova, M. Smogavec, L.A. Schwarz, S. Gorkiewicz, N. Amberg, F. Pauler, C. Knittl-Frank, M. Tassinari, N. Maulide, T. Rülicke, J. Menche, S. Hippenmeyer, G. Novarino, Cell 186 (2023) 1950–1967.e25. date_created: 2023-04-05T08:15:40Z date_published: 2023-04-27T00:00:00Z date_updated: 2024-02-07T08:03:32Z day: '27' ddc: - '570' department: - _id: SiHi - _id: GaNo doi: 10.1016/j.cell.2023.02.037 ec_funded: 1 external_id: isi: - '000991468700001' file: - access_level: open_access checksum: 47e94fbe19e86505b429cb7a5b503ce6 content_type: application/pdf creator: dernst date_created: 2023-05-02T09:26:21Z date_updated: 2023-05-02T09:26:21Z file_id: '12889' file_name: 2023_Cell_Knaus.pdf file_size: 15712841 relation: main_file success: 1 file_date_updated: 2023-05-02T09:26:21Z has_accepted_license: '1' intvolume: ' 186' isi: 1 issue: '9' keyword: - General Biochemistry - Genetics and Molecular Biology language: - iso: eng month: '04' oa: 1 oa_version: Published Version page: 1950-1967.e25 project: - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets - _id: 260018B0-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '725780' name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development - _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 publication: Cell publication_identifier: issn: - 0092-8674 publication_status: published publisher: Elsevier quality_controlled: '1' related_material: link: - description: News on ISTA Website relation: press_release url: https://ista.ac.at/en/news/feed-them-or-lose-them/ record: - id: '13107' relation: dissertation_contains status: public scopus_import: '1' status: public title: Large neutral amino acid levels tune perinatal neuronal excitability and survival tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 186 year: '2023' ... --- _id: '10281' 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 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.' alternative_title: - Special Issue "From Genes to Therapy in Autism Spectrum Disorder" article_number: '1746' article_processing_charge: No article_type: original author: - first_name: Verica full_name: Vasic, Verica last_name: Vasic - first_name: Mattson S.O. full_name: Jones, Mattson S.O. last_name: Jones - first_name: Denise full_name: Haslinger, Denise id: 76922BDA-3D3B-11EA-90BD-A44F3DDC885E last_name: Haslinger - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Michael J. full_name: Schmeisser, Michael J. last_name: Schmeisser - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: Andreas G. full_name: Chiocchetti, Andreas G. last_name: Chiocchetti citation: 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' 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.' 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.' 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.' 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.' short: V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino, A.G. Chiocchetti, Genes 12 (2021). date_created: 2021-11-14T23:01:24Z date_published: 2021-10-30T00:00:00Z date_updated: 2023-08-14T11:46:12Z day: '30' ddc: - '570' department: - _id: GaNo doi: 10.3390/genes12111746 ec_funded: 1 external_id: isi: - '000834044200002' file: - access_level: open_access checksum: 256cb832a9c3051c7dc741f6423b8cbd content_type: application/pdf creator: dernst date_created: 2022-05-16T07:02:27Z date_updated: 2022-05-16T07:02:27Z file_id: '11380' file_name: 2021_Genes_Vasic.pdf file_size: 1335308 relation: main_file success: 1 file_date_updated: 2022-05-16T07:02:27Z has_accepted_license: '1' intvolume: ' 12' isi: 1 issue: '11' language: - iso: eng month: '10' oa: 1 oa_version: Published Version project: - _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 - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets publication: Genes publication_identifier: eissn: - 2073-4425 publication_status: published publisher: MDPI quality_controlled: '1' scopus_import: '1' status: public title: 'Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 12 year: '2021' ... --- _id: '9429' abstract: - lang: eng 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. acknowledged_ssus: - _id: PreCl 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). article_number: '3058' article_processing_charge: No article_type: original author: - first_name: Jasmin full_name: Morandell, Jasmin id: 4739D480-F248-11E8-B48F-1D18A9856A87 last_name: Morandell - first_name: Lena A full_name: Schwarz, Lena A id: 29A8453C-F248-11E8-B48F-1D18A9856A87 last_name: Schwarz - first_name: Bernadette full_name: Basilico, Bernadette id: 36035796-5ACA-11E9-A75E-7AF2E5697425 last_name: Basilico orcid: 0000-0003-1843-3173 - first_name: Saren full_name: Tasciyan, Saren id: 4323B49C-F248-11E8-B48F-1D18A9856A87 last_name: Tasciyan orcid: 0000-0003-1671-393X - first_name: Georgi A full_name: Dimchev, Georgi A id: 38C393BE-F248-11E8-B48F-1D18A9856A87 last_name: Dimchev orcid: 0000-0001-8370-6161 - first_name: Armel full_name: Nicolas, Armel id: 2A103192-F248-11E8-B48F-1D18A9856A87 last_name: Nicolas - first_name: Christoph M full_name: Sommer, Christoph M id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87 last_name: Sommer orcid: 0000-0003-1216-9105 - first_name: Caroline full_name: Kreuzinger, Caroline id: 382077BA-F248-11E8-B48F-1D18A9856A87 last_name: Kreuzinger - first_name: Christoph full_name: Dotter, Christoph id: 4C66542E-F248-11E8-B48F-1D18A9856A87 last_name: Dotter orcid: 0000-0002-9033-9096 - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Zoe full_name: Dobler, Zoe id: D23090A2-9057-11EA-883A-A8396FC7A38F last_name: Dobler - first_name: Emanuele full_name: Cacci, Emanuele last_name: Cacci - first_name: Florian KM full_name: Schur, Florian KM id: 48AD8942-F248-11E8-B48F-1D18A9856A87 last_name: Schur orcid: 0000-0003-4790-8078 - first_name: Johann G full_name: Danzl, Johann G id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87 last_name: Danzl orcid: 0000-0001-8559-3973 - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: 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 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. 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. 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. 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. 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). date_created: 2021-05-28T11:49:46Z date_published: 2021-05-24T00:00:00Z date_updated: 2024-03-28T23:30:23Z day: '24' ddc: - '572' department: - _id: GaNo - _id: JoDa - _id: FlSc - _id: MiSi - _id: LifeSc - _id: Bio doi: 10.1038/s41467-021-23123-x ec_funded: 1 external_id: isi: - '000658769900010' file: - access_level: open_access checksum: 337e0f7959c35ec959984cacdcb472ba content_type: application/pdf creator: kschuh date_created: 2021-05-28T12:39:43Z date_updated: 2021-05-28T12:39:43Z file_id: '9430' file_name: 2021_NatureCommunications_Morandell.pdf file_size: 9358599 relation: main_file success: 1 file_date_updated: 2021-05-28T12:39:43Z has_accepted_license: '1' intvolume: ' 12' isi: 1 issue: '1' keyword: - General Biochemistry - Genetics and Molecular Biology language: - iso: eng month: '05' oa: 1 oa_version: Published Version project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships - _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 - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets - _id: 05A0D778-7A3F-11EA-A408-12923DDC885E grant_number: F07807 name: Neural stem cells in autism and epilepsy - _id: 265CB4D0-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: I03600 name: Optical control of synaptic function via adhesion molecules publication: Nature Communications publication_identifier: eissn: - 2041-1723 publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: link: - relation: press_release url: https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/ record: - id: '7800' relation: earlier_version status: public - id: '12401' relation: dissertation_contains status: public status: public title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 12 year: '2021' ... --- _id: '7800' abstract: - lang: eng 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. acknowledged_ssus: - _id: PreCl article_processing_charge: No author: - first_name: Jasmin full_name: Morandell, Jasmin id: 4739D480-F248-11E8-B48F-1D18A9856A87 last_name: Morandell - first_name: Lena A full_name: Schwarz, Lena A id: 29A8453C-F248-11E8-B48F-1D18A9856A87 last_name: Schwarz - first_name: Bernadette full_name: Basilico, Bernadette id: 36035796-5ACA-11E9-A75E-7AF2E5697425 last_name: Basilico orcid: 0000-0003-1843-3173 - first_name: Saren full_name: Tasciyan, Saren id: 4323B49C-F248-11E8-B48F-1D18A9856A87 last_name: Tasciyan orcid: 0000-0003-1671-393X - first_name: Armel full_name: Nicolas, Armel id: 2A103192-F248-11E8-B48F-1D18A9856A87 last_name: Nicolas - first_name: Christoph M full_name: Sommer, Christoph M id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87 last_name: Sommer orcid: 0000-0003-1216-9105 - first_name: Caroline full_name: Kreuzinger, Caroline id: 382077BA-F248-11E8-B48F-1D18A9856A87 last_name: Kreuzinger - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Zoe full_name: Dobler, Zoe id: D23090A2-9057-11EA-883A-A8396FC7A38F last_name: Dobler - first_name: Emanuele full_name: Cacci, Emanuele last_name: Cacci - first_name: Johann G full_name: Danzl, Johann G id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87 last_name: Danzl orcid: 0000-0001-8559-3973 - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: 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 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 . 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. 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 . 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.). date_created: 2020-05-05T14:31:33Z date_published: 2020-01-11T00:00:00Z date_updated: 2024-03-28T23:30:14Z day: '11' ddc: - '570' department: - _id: JoDa - _id: GaNo - _id: LifeSc doi: '10.1101/2020.01.10.902064 ' file: - access_level: open_access checksum: c6799ab5daba80efe8e2ed63c15f8c81 content_type: application/pdf creator: rsix date_created: 2020-05-05T14:31:19Z date_updated: 2020-07-14T12:48:03Z file_id: '7801' file_name: 2020.01.10.902064v1.full.pdf file_size: 2931370 relation: main_file file_date_updated: 2020-07-14T12:48:03Z has_accepted_license: '1' language: - iso: eng month: '01' oa: 1 oa_version: Preprint project: - _id: 265CB4D0-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: I03600 name: Optical control of synaptic function via adhesion molecules - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets publication: bioRxiv publication_status: submitted publisher: Cold Spring Harbor Laboratory related_material: record: - id: '9429' relation: later_version status: public - id: '8620' relation: dissertation_contains status: public status: public title: Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: preprint user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ... --- _id: '7414' article_processing_charge: No article_type: original author: - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Knaus L, Tarlungeanu D-C, Novarino G. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. 2019;29(Supplement 6):S11. doi:10.1016/j.euroneuro.2019.09.039 apa: Knaus, L., Tarlungeanu, D.-C., & Novarino, G. (2019). S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.039 chicago: Knaus, Lisa, Dora-Clara Tarlungeanu, and Gaia Novarino. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.039. ieee: L. Knaus, D.-C. Tarlungeanu, and G. Novarino, “S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly,” European Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, p. S11, 2019. ista: Knaus L, Tarlungeanu D-C, Novarino G. 2019. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. 29(Supplement 6), S11. mla: Knaus, Lisa, et al. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” European Neuropsychopharmacology, vol. 29, no. Supplement 6, Elsevier, 2019, p. S11, doi:10.1016/j.euroneuro.2019.09.039. short: L. Knaus, D.-C. Tarlungeanu, G. Novarino, European Neuropsychopharmacology 29 (2019) S11. date_created: 2020-01-30T10:06:15Z date_published: 2019-12-13T00:00:00Z date_updated: 2023-09-07T14:55:23Z day: '13' department: - _id: GaNo doi: 10.1016/j.euroneuro.2019.09.039 external_id: isi: - '000502657500020' intvolume: ' 29' isi: 1 issue: Supplement 6 language: - iso: eng month: '12' oa_version: None page: S11 publication: European Neuropsychopharmacology publication_identifier: issn: - 0924-977X publication_status: published publisher: Elsevier quality_controlled: '1' status: public title: S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 29 year: '2019' ...