[{"title":"Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity","abstract":[{"text":"Structural and functional differences between brain hemispheres are a common feature of animal nervous systems with reduced bilateral asymmetry often linked to impaired cognitive performance. How neuronal left-right asymmetry is initiated and integrated into a bilaterally symmetrical ground pattern is poorly understood. Here, we show that the directional asymmetry of a Drosophila central brain circuit originates from axonal interactions of two types of bilateral pioneer neurons. Subsequent recruitment of neighboring neurons into the asymmetric neuropil primordium results in hemisphere-specific microcircuits. Circuit lateralization requires dynamic expression of the cell adhesion molecule Fasciclin 2 to maintain structural plasticity in axonal remodeling. Reduced circuit asymmetry following cell type–specific Fasciclin 2 manipulation affects adult brain function. These results reveal an unexpected degree of developmental plasticity of late-born Drosophila neurons in the formation of a circuit node via the lateralized recruitment of symmetric circuit components.","lang":"eng"}],"has_accepted_license":"1","author":[{"full_name":"Markovitsch, Johann W.","last_name":"Markovitsch","first_name":"Johann W."},{"last_name":"Mitić","full_name":"Mitić, Daniel","first_name":"Daniel"},{"first_name":"Alisa","full_name":"Del Pilar Jiménez García, Alisa","last_name":"Del Pilar Jiménez García"},{"full_name":"Zane, Alsberga","id":"60f7509a-f652-11ea-9d86-b963d6490d7c","last_name":"Zane","first_name":"Alsberga","orcid":"0009-0003-0415-7603"},{"first_name":"Sarah","last_name":"Kainz","full_name":"Kainz, Sarah"},{"first_name":"Rashmit","last_name":"Kaur","full_name":"Kaur, Rashmit"},{"first_name":"Thomas","full_name":"Hummel, Thomas","last_name":"Hummel"}],"doi":"10.1126/sciadv.aea6020","DOAJ_listed":"1","quality_controlled":"1","scopus_import":"1","issue":"13","date_published":"2026-03-27T00:00:00Z","citation":{"ista":"Markovitsch JW, Mitić D, Del Pilar Jiménez García A, Zane A, Kainz S, Kaur R, Hummel T. 2026. Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity. Science Advances. 12(13), eaea6020.","apa":"Markovitsch, J. W., Mitić, D., Del Pilar Jiménez García, A., Zane, A., Kainz, S., Kaur, R., &#38; Hummel, T. (2026). Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity. <i>Science Advances</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/sciadv.aea6020\">https://doi.org/10.1126/sciadv.aea6020</a>","ama":"Markovitsch JW, Mitić D, Del Pilar Jiménez García A, et al. Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity. <i>Science Advances</i>. 2026;12(13). doi:<a href=\"https://doi.org/10.1126/sciadv.aea6020\">10.1126/sciadv.aea6020</a>","short":"J.W. Markovitsch, D. Mitić, A. Del Pilar Jiménez García, A. Zane, S. Kainz, R. Kaur, T. Hummel, Science Advances 12 (2026).","ieee":"J. W. Markovitsch <i>et al.</i>, “Sequential formation of Drosophila circuit asymmetry via prolonged structural plasticity,” <i>Science Advances</i>, vol. 12, no. 13. American Association for the Advancement of Science, 2026.","chicago":"Markovitsch, Johann W., Daniel Mitić, Alisa Del Pilar Jiménez García, Alsberga Zane, Sarah Kainz, Rashmit Kaur, and Thomas Hummel. “Sequential Formation of Drosophila Circuit Asymmetry via Prolonged Structural Plasticity.” <i>Science Advances</i>. American Association for the Advancement of Science, 2026. <a href=\"https://doi.org/10.1126/sciadv.aea6020\">https://doi.org/10.1126/sciadv.aea6020</a>.","mla":"Markovitsch, Johann W., et al. “Sequential Formation of Drosophila Circuit Asymmetry via Prolonged Structural Plasticity.” <i>Science Advances</i>, vol. 12, no. 13, eaea6020, American Association for the Advancement of Science, 2026, doi:<a href=\"https://doi.org/10.1126/sciadv.aea6020\">10.1126/sciadv.aea6020</a>."},"publication_identifier":{"eissn":["2375-2548"]},"publisher":"American Association for the Advancement of Science","_id":"21707","volume":12,"article_processing_charge":"Yes","file_date_updated":"2026-05-04T09:16:36Z","intvolume":"        12","oa_version":"Published Version","article_number":"eaea6020","ddc":["570"],"status":"public","publication":"Science Advances","OA_type":"gold","date_created":"2026-04-12T22:01:48Z","department":[{"_id":"MiSi"},{"_id":"GradSch"}],"acknowledgement":"We thank I. Salecker (Flybow), B. Altenhein (Fas2-Gal4Mz507), A. Nose (UAS-intra- and extra-Fas2::YFP), and C. S. Goodman (UAS-Fas2PEST+/−), as well as the Bloomington Stock Center for providing materials and fly stocks. We thank S. Waddell and the lab, especially B. Senapati, for providing the opportunity to conduct memory experiments at the CNCB, University of Oxford, and for supervision and discussions during this period. We also thank W. Kallina, S. Ilgerl, D. Bartel, A. Grimm, and A. Litin for technical support and the Hummel Lab for stimulating discussions and critical comments on the manuscript. We acknowledge the early exploratory work of A. Mattia, S. Trkulja, C. Schönherr, S. Bogner, B. Simpson, L. Tomasek, H. Roth, H. Vokač, R. Gredler, F. Kapelari, T. Kolarova, C. Ignitsch, Á. Bautista-Soldevila, and M. Kassem.\r\nThis research was funded by the University of Vienna, the Vienna Doctoral School Cognition, Behaviour and Neuroscience (uni:docs fellowship) (to J.W.M.) and by the Austrian Science Fund (FWF) (Cluster of Excellence Neuronal Circuits in Health and Disease, grant DOI 10.55776/COE16; https://www.fwf.ac.at/en/research-radar/10.55776/COE16) (to T.H.). For open access purposes, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.","language":[{"iso":"eng"}],"month":"03","date_updated":"2026-05-04T09:18:06Z","oa":1,"OA_place":"publisher","file":[{"checksum":"3eed470fe73e53d2a8d55d6fba6934e3","relation":"main_file","creator":"dernst","file_size":11101140,"access_level":"open_access","date_updated":"2026-05-04T09:16:36Z","content_type":"application/pdf","file_id":"21786","file_name":"2026_ScienceAdv_Markovitsch.pdf","success":1,"date_created":"2026-05-04T09:16:36Z"}],"type":"journal_article","article_type":"original","publication_status":"published","year":"2026","day":"27","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","tmp":{"short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png"}},{"article_number":"e2504064122","date_created":"2025-09-07T22:01:32Z","OA_type":"hybrid","publication":"Proceedings of the National Academy of Sciences","status":"public","PlanS_conform":"1","ddc":["570"],"related_material":{"link":[{"url":"https://github.com/mehmetcanucar/Self-generated-chemotaxis","relation":"software"}]},"oa":1,"language":[{"iso":"eng"}],"date_updated":"2026-05-20T08:59:54Z","month":"08","acknowledgement":"We thank all members of the M.S. and E.H. groups for stimulating discussions.We thank the Imaging and Optics facility, the Pre-clinical and Lab Support facility of the Institute of Science and Technology Austria for their excellent support and provided resources for the experimental research. In particular, we thank Jack Merrin from the Nanofabrication facility who generated the microfabricated channel used in this study. This work received funding fromt he European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 851288 to E.H.). M.C.U.is funded by a University of Sheffield Strategic Research Fellowship in the Physics of Life and Quantitative Biology.","department":[{"_id":"EdHa"},{"_id":"MiSi"}],"isi":1,"pmid":1,"tmp":{"short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png"},"year":"2025","day":"26","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_status":"published","article_type":"original","type":"journal_article","file":[{"relation":"main_file","creator":"dernst","checksum":"b36abd92673b6d76376fc9434bad52cc","access_level":"open_access","date_updated":"2025-09-08T07:23:29Z","file_size":16069140,"file_name":"2025_PNAS_Ucar.pdf","success":1,"content_type":"application/pdf","file_id":"20307","date_created":"2025-09-08T07:23:29Z"}],"OA_place":"publisher","doi":"10.1073/pnas.2504064122","author":[{"orcid":"0000-0003-0506-4217","first_name":"Mehmet C","last_name":"Ucar","id":"50B2A802-6007-11E9-A42B-EB23E6697425","full_name":"Ucar, Mehmet C"},{"orcid":"0009-0003-0415-7603","first_name":"Alsberga","full_name":"Zane, Alsberga","id":"60f7509a-f652-11ea-9d86-b963d6490d7c","last_name":"Zane"},{"id":"2CC12E8C-F248-11E8-B48F-1D18A9856A87","last_name":"Alanko","full_name":"Alanko, Jonna H","orcid":"0000-0002-7698-3061","first_name":"Jonna H"},{"first_name":"Michael K","orcid":"0000-0002-6620-9179","last_name":"Sixt","id":"41E9FBEA-F248-11E8-B48F-1D18A9856A87","full_name":"Sixt, Michael K"},{"orcid":"0000-0001-6005-1561","first_name":"Edouard B","full_name":"Hannezo, Edouard B","last_name":"Hannezo","id":"3A9DB764-F248-11E8-B48F-1D18A9856A87"}],"has_accepted_license":"1","title":"Self-generated chemotaxis of mixed cell populations","abstract":[{"text":"Cell and tissue movement in development, cancer invasion, and immune response relies on chemical or mechanical guidance cues. In many systems, this behavior is locally directed by self-generated signaling gradients rather than long-range, prepatterned cues. However, how heterogeneous mixtures of cells interact nonreciprocally and navigate through self-generated gradients remains largely unexplored. Here, we introduce a theoretical framework for the self-organized chemotaxis of heterogeneous cell populations. We find that the relative chemotactic sensitivities of different cell populations control their long-time coupling and comigration dynamics, with boundary conditions such as external cell and attractant reservoirs substantially influencing the migration patterns. Our model predicts an optimal parameter regime that enables robust and colocalized migration. We test our theoretical predictions with in vitro experiments demonstrating the comigration of distinct immune cell populations, and quantitatively reproduce observed migration patterns under wild-type and perturbed conditions. Interestingly, immune cell comigration occurs close to the predicted optimal regime. Finally, we incorporate mechanical interactions into our framework, revealing a nontrivial interplay between chemotactic and mechanical nonreciprocity in driving collective migration. Together, our findings suggest that self-generated chemotaxis is a robust strategy for the navigation of mixed cell populations.","lang":"eng"}],"ec_funded":1,"issue":"34","quality_controlled":"1","corr_author":"1","scopus_import":"1","external_id":{"isi":["001562181600001"],"pmid":["40838890"]},"article_processing_charge":"Yes (in subscription journal)","volume":122,"_id":"20289","APC_amount":"5766,07 EUR","publisher":"National Academy of Sciences","date_published":"2025-08-26T00:00:00Z","acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"},{"_id":"LifeSc"},{"_id":"NanoFab"}],"publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"citation":{"mla":"Ucar, Mehmet C., et al. “Self-Generated Chemotaxis of Mixed Cell Populations.” <i>Proceedings of the National Academy of Sciences</i>, vol. 122, no. 34, e2504064122, National Academy of Sciences, 2025, doi:<a href=\"https://doi.org/10.1073/pnas.2504064122\">10.1073/pnas.2504064122</a>.","chicago":"Ucar, Mehmet C, Alsberga Zane, Jonna H Alanko, Michael K Sixt, and Edouard B Hannezo. “Self-Generated Chemotaxis of Mixed Cell Populations.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2025. <a href=\"https://doi.org/10.1073/pnas.2504064122\">https://doi.org/10.1073/pnas.2504064122</a>.","ieee":"M. C. Ucar, A. Zane, J. H. Alanko, M. K. Sixt, and E. B. Hannezo, “Self-generated chemotaxis of mixed cell populations,” <i>Proceedings of the National Academy of Sciences</i>, vol. 122, no. 34. National Academy of Sciences, 2025.","short":"M.C. Ucar, A. Zane, J.H. Alanko, M.K. Sixt, E.B. Hannezo, Proceedings of the National Academy of Sciences 122 (2025).","ista":"Ucar MC, Zane A, Alanko JH, Sixt MK, Hannezo EB. 2025. Self-generated chemotaxis of mixed cell populations. Proceedings of the National Academy of Sciences. 122(34), e2504064122.","ama":"Ucar MC, Zane A, Alanko JH, Sixt MK, Hannezo EB. Self-generated chemotaxis of mixed cell populations. <i>Proceedings of the National Academy of Sciences</i>. 2025;122(34). doi:<a href=\"https://doi.org/10.1073/pnas.2504064122\">10.1073/pnas.2504064122</a>","apa":"Ucar, M. C., Zane, A., Alanko, J. H., Sixt, M. K., &#38; Hannezo, E. B. (2025). Self-generated chemotaxis of mixed cell populations. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2504064122\">https://doi.org/10.1073/pnas.2504064122</a>"},"project":[{"name":"Design Principles of Branching Morphogenesis","grant_number":"851288","_id":"05943252-7A3F-11EA-A408-12923DDC885E","call_identifier":"H2020"}],"oa_version":"Published Version","intvolume":"       122","file_date_updated":"2025-09-08T07:23:29Z"}]