[{"oa_version":"None","abstract":[{"lang":"eng","text":"Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characteristics govern cellular response patterns, we here introduce an in vitro system allowing to track migratory responses of DCs to precisely controlled immobilized gradients of CCL21. We find that haptotactic sensing depends on the absolute CCL21 concentration and local steepness of the gradient, consistent with a scenario where DC directionality is governed by the signal-to-noise ratio of CCL21 binding to the receptor CCR7. We find that the conditions for optimal DC guidance are perfectly provided by the CCL21 gradients we measure in vivo. Furthermore, we find that CCR7 signal termination by the G-protein-coupled receptor kinase 6 (GRK6) is crucial for haptotactic but dispensable for chemotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. These findings suggest that stable, tissue-bound CCL21 gradients as sustainable “roads” ensure optimal guidance in vivo."}],"month":"05","intvolume":" 27","scopus_import":1,"language":[{"iso":"eng"}],"publication_identifier":{"issn":["09609822"]},"publication_status":"published","issue":"9","volume":27,"ec_funded":1,"_id":"674","status":"public","type":"journal_article","date_updated":"2023-02-23T12:50:44Z","department":[{"_id":"MiSi"},{"_id":"Bio"},{"_id":"NanoFab"}],"quality_controlled":"1","publisher":"Cell Press","day":"09","publication":"Current Biology","year":"2017","doi":"10.1016/j.cub.2017.04.004","date_published":"2017-05-09T00:00:00Z","date_created":"2018-12-11T11:47:51Z","page":"1314 - 1325","project":[{"_id":"25681D80-B435-11E9-9278-68D0E5697425","call_identifier":"FP7","grant_number":"291734","name":"International IST Postdoc Fellowship Programme"},{"grant_number":"Y 564-B12","name":"Cytoskeletal force generation and transduction of leukocytes (FWF)","call_identifier":"FWF","_id":"25A8E5EA-B435-11E9-9278-68D0E5697425"}],"user_id":"4435EBFC-F248-11E8-B48F-1D18A9856A87","citation":{"ista":"Schwarz J, Bierbaum V, Vaahtomeri K, Hauschild R, Brown M, de Vries I, Leithner AF, Reversat A, Merrin J, Tarrant T, Bollenbach MT, Sixt MK. 2017. Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6. Current Biology. 27(9), 1314–1325.","chicago":"Schwarz, Jan, Veronika Bierbaum, Kari Vaahtomeri, Robert Hauschild, Markus Brown, Ingrid de Vries, Alexander F Leithner, et al. “Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal to Noise Ratio and Dependent on GRK6.” Current Biology. Cell Press, 2017. https://doi.org/10.1016/j.cub.2017.04.004.","apa":"Schwarz, J., Bierbaum, V., Vaahtomeri, K., Hauschild, R., Brown, M., de Vries, I., … Sixt, M. K. (2017). Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6. Current Biology. Cell Press. https://doi.org/10.1016/j.cub.2017.04.004","ama":"Schwarz J, Bierbaum V, Vaahtomeri K, et al. Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6. Current Biology. 2017;27(9):1314-1325. doi:10.1016/j.cub.2017.04.004","ieee":"J. Schwarz et al., “Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6,” Current Biology, vol. 27, no. 9. Cell Press, pp. 1314–1325, 2017.","short":"J. Schwarz, V. Bierbaum, K. Vaahtomeri, R. Hauschild, M. Brown, I. de Vries, A.F. Leithner, A. Reversat, J. Merrin, T. Tarrant, M.T. Bollenbach, M.K. Sixt, Current Biology 27 (2017) 1314–1325.","mla":"Schwarz, Jan, et al. “Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal to Noise Ratio and Dependent on GRK6.” Current Biology, vol. 27, no. 9, Cell Press, 2017, pp. 1314–25, doi:10.1016/j.cub.2017.04.004."},"title":"Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6","author":[{"first_name":"Jan","id":"346C1EC6-F248-11E8-B48F-1D18A9856A87","last_name":"Schwarz","full_name":"Schwarz, Jan"},{"full_name":"Bierbaum, Veronika","last_name":"Bierbaum","first_name":"Veronika","id":"3FD04378-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Kari","id":"368EE576-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-7829-3518","full_name":"Vaahtomeri, Kari","last_name":"Vaahtomeri"},{"id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","first_name":"Robert","full_name":"Hauschild, Robert","orcid":"0000-0001-9843-3522","last_name":"Hauschild"},{"full_name":"Brown, Markus","last_name":"Brown","first_name":"Markus","id":"3DAB9AFC-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Ingrid","id":"4C7D837E-F248-11E8-B48F-1D18A9856A87","last_name":"De Vries","full_name":"De Vries, Ingrid"},{"full_name":"Leithner, Alexander F","last_name":"Leithner","id":"3B1B77E4-F248-11E8-B48F-1D18A9856A87","first_name":"Alexander F"},{"full_name":"Reversat, Anne","orcid":"0000-0003-0666-8928","last_name":"Reversat","first_name":"Anne","id":"35B76592-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Jack","id":"4515C308-F248-11E8-B48F-1D18A9856A87","full_name":"Merrin, Jack","orcid":"0000-0001-5145-4609","last_name":"Merrin"},{"first_name":"Teresa","last_name":"Tarrant","full_name":"Tarrant, Teresa"},{"last_name":"Bollenbach","orcid":"0000-0003-4398-476X","full_name":"Bollenbach, Tobias","first_name":"Tobias","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Sixt","full_name":"Sixt, Michael K","orcid":"0000-0002-6620-9179","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","first_name":"Michael K"}],"publist_id":"7050"},{"ddc":["579"],"date_updated":"2021-01-12T06:48:41Z","department":[{"_id":"MiSi"},{"_id":"NanoFab"},{"_id":"Bio"},{"_id":"ToBo"}],"file_date_updated":"2018-12-12T10:09:32Z","_id":"1154","status":"public","pubrep_id":"744","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)"},"file":[{"file_id":"4756","relation":"main_file","access_level":"open_access","content_type":"application/pdf","file_name":"IST-2017-744-v1+1_srep36440.pdf","date_created":"2018-12-12T10:09:32Z","creator":"system","file_size":2353456,"date_updated":"2018-12-12T10:09:32Z"}],"language":[{"iso":"eng"}],"publication_status":"published","volume":6,"ec_funded":1,"oa_version":"Published Version","abstract":[{"text":"Cellular locomotion is a central hallmark of eukaryotic life. It is governed by cell-extrinsic molecular factors, which can either emerge in the soluble phase or as immobilized, often adhesive ligands. To encode for direction, every cue must be present as a spatial or temporal gradient. Here, we developed a microfluidic chamber that allows measurement of cell migration in combined response to surface immobilized and soluble molecular gradients. As a proof of principle we study the response of dendritic cells to their major guidance cues, chemokines. The majority of data on chemokine gradient sensing is based on in vitro studies employing soluble gradients. Despite evidence suggesting that in vivo chemokines are often immobilized to sugar residues, limited information is available how cells respond to immobilized chemokines. We tracked migration of dendritic cells towards immobilized gradients of the chemokine CCL21 and varying superimposed soluble gradients of CCL19. Differential migratory patterns illustrate the potential of our setup to quantitatively study the competitive response to both types of gradients. Beyond chemokines our approach is broadly applicable to alternative systems of chemo- and haptotaxis such as cells migrating along gradients of adhesion receptor ligands vs. any soluble cue. \r\n","lang":"eng"}],"month":"11","intvolume":" 6","scopus_import":1,"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","citation":{"mla":"Schwarz, Jan, et al. “A Microfluidic Device for Measuring Cell Migration towards Substrate Bound and Soluble Chemokine Gradients.” Scientific Reports, vol. 6, 36440, Nature Publishing Group, 2016, doi:10.1038/srep36440.","short":"J. Schwarz, V. Bierbaum, J. Merrin, T. Frank, R. Hauschild, M.T. Bollenbach, S. Tay, M.K. Sixt, M. Mehling, Scientific Reports 6 (2016).","ieee":"J. Schwarz et al., “A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients,” Scientific Reports, vol. 6. Nature Publishing Group, 2016.","apa":"Schwarz, J., Bierbaum, V., Merrin, J., Frank, T., Hauschild, R., Bollenbach, M. T., … Mehling, M. (2016). A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. Nature Publishing Group. https://doi.org/10.1038/srep36440","ama":"Schwarz J, Bierbaum V, Merrin J, et al. A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. 2016;6. doi:10.1038/srep36440","chicago":"Schwarz, Jan, Veronika Bierbaum, Jack Merrin, Tino Frank, Robert Hauschild, Mark Tobias Bollenbach, Savaş Tay, Michael K Sixt, and Matthias Mehling. “A Microfluidic Device for Measuring Cell Migration towards Substrate Bound and Soluble Chemokine Gradients.” Scientific Reports. Nature Publishing Group, 2016. https://doi.org/10.1038/srep36440.","ista":"Schwarz J, Bierbaum V, Merrin J, Frank T, Hauschild R, Bollenbach MT, Tay S, Sixt MK, Mehling M. 2016. A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients. Scientific Reports. 6, 36440."},"title":"A microfluidic device for measuring cell migration towards substrate bound and soluble chemokine gradients","publist_id":"6204","author":[{"id":"346C1EC6-F248-11E8-B48F-1D18A9856A87","first_name":"Jan","full_name":"Schwarz, Jan","last_name":"Schwarz"},{"first_name":"Veronika","id":"3FD04378-F248-11E8-B48F-1D18A9856A87","last_name":"Bierbaum","full_name":"Bierbaum, Veronika"},{"id":"4515C308-F248-11E8-B48F-1D18A9856A87","first_name":"Jack","last_name":"Merrin","full_name":"Merrin, Jack","orcid":"0000-0001-5145-4609"},{"last_name":"Frank","full_name":"Frank, Tino","first_name":"Tino"},{"id":"4E01D6B4-F248-11E8-B48F-1D18A9856A87","first_name":"Robert","full_name":"Hauschild, Robert","orcid":"0000-0001-9843-3522","last_name":"Hauschild"},{"first_name":"Mark Tobias","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-4398-476X","full_name":"Bollenbach, Mark Tobias","last_name":"Bollenbach"},{"first_name":"Savaş","last_name":"Tay","full_name":"Tay, Savaş"},{"first_name":"Michael K","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-6620-9179","full_name":"Sixt, Michael K","last_name":"Sixt"},{"id":"3C23B994-F248-11E8-B48F-1D18A9856A87","first_name":"Matthias","last_name":"Mehling","full_name":"Mehling, Matthias","orcid":"0000-0001-8599-1226"}],"article_number":"36440","project":[{"call_identifier":"FP7","_id":"25A603A2-B435-11E9-9278-68D0E5697425","name":"Cytoskeletal force generation and force transduction of migrating leukocytes (EU)","grant_number":"281556"},{"name":"Cytoskeletal force generation and transduction of leukocytes (FWF)","grant_number":"Y 564-B12","call_identifier":"FWF","_id":"25A8E5EA-B435-11E9-9278-68D0E5697425"}],"day":"07","publication":"Scientific Reports","has_accepted_license":"1","year":"2016","date_published":"2016-11-07T00:00:00Z","doi":"10.1038/srep36440","date_created":"2018-12-11T11:50:27Z","acknowledgement":"This work was supported by the Swiss National Science Foundation (Ambizione fellowship; PZ00P3-154733 to M.M.), the Swiss Multiple Sclerosis Society (research support to M.M.), a fellowship from the Boehringer Ingelheim Fonds (BIF) to J.S., the European Research Council (grant ERC GA 281556) and a START award from the Austrian Science Foundation (FWF) to M.S. #BioimagingFacility","quality_controlled":"1","publisher":"Nature Publishing Group","oa":1},{"issue":"6","doi":"10.1088/1478-3975/12/6/066003","volume":12,"date_published":"2015-09-25T00:00:00Z","date_created":"2018-12-11T11:52:33Z","publication_status":"published","year":"2015","day":"25","language":[{"iso":"eng"}],"publication":"Physical Biology","publisher":"IOP Publishing Ltd.","scopus_import":1,"quality_controlled":"1","month":"09","intvolume":" 12","abstract":[{"text":"In growing cells, protein synthesis and cell growth are typically not synchronous, and, thus, protein concentrations vary over the cell division cycle. We have developed a theoretical description of genetic regulatory systems in bacteria that explicitly considers the cell division cycle to investigate its impact on gene expression. We calculate the cell-to-cell variations arising from cells being at different stages in the division cycle for unregulated genes and for basic regulatory mechanisms. These variations contribute to the extrinsic noise observed in single-cell experiments, and are most significant for proteins with short lifetimes. Negative autoregulation buffers against variation of protein concentration over the division cycle, but the effect is found to be relatively weak. Stronger buffering is achieved by an increased protein lifetime. Positive autoregulation can strongly amplify such variation if the parameters are set to values that lead to resonance-like behaviour. For cooperative positive autoregulation, the concentration variation over the division cycle diminishes the parameter region of bistability and modulates the switching times between the two stable states. The same effects are seen for a two-gene mutual-repression toggle switch. By contrast, an oscillatory circuit, the repressilator, is only weakly affected by the division cycle.","lang":"eng"}],"oa_version":"None","author":[{"last_name":"Bierbaum","full_name":"Bierbaum, Veronika","id":"3FD04378-F248-11E8-B48F-1D18A9856A87","first_name":"Veronika"},{"last_name":"Klumpp","full_name":"Klumpp, Stefan","first_name":"Stefan"}],"publist_id":"5641","department":[{"_id":"MiSi"}],"title":"Impact of the cell division cycle on gene circuits","citation":{"ista":"Bierbaum V, Klumpp S. 2015. Impact of the cell division cycle on gene circuits. Physical Biology. 12(6), 066003.","chicago":"Bierbaum, Veronika, and Stefan Klumpp. “Impact of the Cell Division Cycle on Gene Circuits.” Physical Biology. IOP Publishing Ltd., 2015. https://doi.org/10.1088/1478-3975/12/6/066003.","apa":"Bierbaum, V., & Klumpp, S. (2015). Impact of the cell division cycle on gene circuits. Physical Biology. IOP Publishing Ltd. https://doi.org/10.1088/1478-3975/12/6/066003","ama":"Bierbaum V, Klumpp S. Impact of the cell division cycle on gene circuits. Physical Biology. 2015;12(6). doi:10.1088/1478-3975/12/6/066003","short":"V. Bierbaum, S. Klumpp, Physical Biology 12 (2015).","ieee":"V. Bierbaum and S. Klumpp, “Impact of the cell division cycle on gene circuits,” Physical Biology, vol. 12, no. 6. IOP Publishing Ltd., 2015.","mla":"Bierbaum, Veronika, and Stefan Klumpp. “Impact of the Cell Division Cycle on Gene Circuits.” Physical Biology, vol. 12, no. 6, 066003, IOP Publishing Ltd., 2015, doi:10.1088/1478-3975/12/6/066003."},"date_updated":"2021-01-12T06:51:25Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","type":"journal_article","status":"public","_id":"1530","article_number":"066003"}]