{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T02:46:03Z","timestamp":1772505963344,"version":"3.50.1"},"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003006","name":"ETH Zurich","doi-asserted-by":"crossref","award":["ETH\u201324 19\u201302"],"award-info":[{"award-number":["ETH\u201324 19\u201302"]}],"id":[{"id":"10.13039\/501100003006","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>During brain development, billions of axons must navigate over multiple spatial scales to reach specific neuronal targets, and so build the processing circuits that generate the intelligent behavior of animals. However, the limited information capacity of the zygotic genome puts a strong constraint on how, and which, axonal routes can be encoded. We propose and validate a mechanism of development that can provide an efficient encoding of this global wiring task. The key principle, confirmed through simulation, is that basic constraints on mitoses of neural stem cells\u2014that mitotic daughters have similar gene expression to their parent and do not stray far from one another\u2014induce a global hierarchical map of nested regions, each marked by the expression profile of its common progenitor population. Thus, a traversal of the lineal hierarchy generates a systematic sequence of expression profiles that traces a staged route, which growth cones can follow to their remote targets. We have analyzed gene expression data of developing and adult mouse brains published by the Allen Institute for Brain Science, and found them consistent with our simulations: gene expression indeed partitions the brain into a global spatial hierarchy of nested contiguous regions that is stable at least from embryonic day 11.5 to postnatal day 56. We use this experimental data to demonstrate that our axonal guidance algorithm is able to robustly extend arbors over long distances to specific targets, and that these connections result in a qualitatively plausible connectome. We conclude that, paradoxically, cell division may be the key to uniting the neurons of the brain.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010382","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T13:30:27Z","timestamp":1661434227000},"page":"e1010382","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Constructive connectomics: How neuronal axons get from here to there using gene-expression maps derived from their family trees"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6113-7823","authenticated-orcid":true,"given":"Stan","family":"Kerstjens","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6676-2863","authenticated-orcid":true,"given":"Gabriela","family":"Michel","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5704-099X","authenticated-orcid":true,"given":"Rodney J.","family":"Douglas","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"issue":"1","key":"pcbi.1010382.ref001","first-page":"3903","volume":"10","author":"MW Reimann","journal-title":"A Null Model of the Mouse Whole-Neocortex Micro-Connectome"},{"issue":"7495","key":"pcbi.1010382.ref002","first-page":"207","volume":"508","author":"SW Oh","journal-title":"A Mesoscale Connectome of the Mouse Brain"},{"issue":"7781","key":"pcbi.1010382.ref003","first-page":"195","volume":"575","author":"JA Harris","journal-title":"Hierarchical Organization of Cortical and Thalamic Connectivity"},{"issue":"1","key":"pcbi.1010382.ref004","first-page":"1","volume":"71","author":"AW Toga","journal-title":"Mapping the Human Connectome"},{"key":"pcbi.1010382.ref005","first-page":"118543","volume":"244","author":"JS Elam","journal-title":"The Human Connectome Project: A Retrospective"},{"issue":"1668","key":"pcbi.1010382.ref006","first-page":"20140173","volume":"370","author":"O Sporns","journal-title":"Cerebral Cartography and Connectomics"},{"issue":"3","key":"pcbi.1010382.ref007","first-page":"730","volume":"174","author":"Z Zheng","journal-title":"A Complete Electron Microscopy Volume of the Brain of Adult Drosophila Melanogaster"},{"key":"pcbi.1010382.ref008","first-page":"e57443","volume":"9","author":"LK Scheffer","journal-title":"A Connectome and Analysis of the Adult Drosophila Central Brain"},{"issue":"1","key":"pcbi.1010382.ref009","first-page":"17","volume":"24","author":"NT Markov","journal-title":"A Weighted and Directed Interareal Connectivity Matrix for Macaque Cerebral Cortex"},{"issue":"3","key":"pcbi.1010382.ref010","first-page":"698","volume":"97","author":"R G\u0103m\u0103nu\u0163","journal-title":"The Mouse Cortical Connectome, Characterized by an Ultra-Dense Cortical Graph, Maintains Specificity by Distinct Connectivity Profiles"},{"key":"pcbi.1010382.ref011","volume":"15","author":"C Belmonte-Mateos","journal-title":"From Cell States to Cell Fates: How Cell Proliferation and Neuronal Differentiation Are Coordinated During Embryonic Development"},{"key":"pcbi.1010382.ref012","unstructured":"Rubenstein JLR, Rakic P. Patterning and Cell Type Specification in the Developing CNS and PNS. Elsevier;. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/C20110076858."},{"key":"pcbi.1010382.ref013","unstructured":"Price DJ, Mason A, Kind P, John O Jarman. Building Brains: An Introduction to Neural Development;. 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