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In this study, using human brain organoids and mouse models, we show that loss of\n                  <jats:italic>NDE1<\/jats:italic>\n                  , a gene closely associated with microcephaly, disrupts progenitor identity, prolongs mitosis, and alters regional patterning in the forebrain.\n                  <jats:italic>NDE1<\/jats:italic>\n                  knockout leads to a caudal identity shift of neural progenitor cells in the organoids and mouse brains, coinciding with aberrant ERK signaling. Notably, downstream activation of the ERK pathway restored rostral\n                  <jats:italic>PAX6<\/jats:italic>\n                  expression in human brain organoids. Parallel analyses of\n                  <jats:italic>Nde1<\/jats:italic>\n                  knockout mice confirmed disrupted regional patterning of the forebrain. Together, our data establish\n                  <jats:italic>NDE1<\/jats:italic>\n                  as a critical regulator of early human brain regionalization and elucidate molecular mechanisms underlying the structural abnormalities observed in\n                  <jats:italic>NDE1<\/jats:italic>\n                  -associated microcephaly.\n                <\/jats:p>","DOI":"10.1101\/2025.08.12.669854","type":"posted-content","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T07:15:22Z","timestamp":1755069322000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural Progenitors as a Novel Pathogenic Mechanism in Microcephaly"],"prefix":"10.64898","author":[{"given":"Rami Yair","family":"Tshuva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeyoon","family":"Bok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mio","family":"Nonaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xufeng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bidisha","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditya","family":"Kshirsagar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsviya","family":"Olender","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miri","family":"Danan-Gotthold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamar","family":"Sapir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianping","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7560-9599","authenticated-orcid":false,"given":"Orly","family":"Reiner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110505250927000_2025.08.12.669854v3.1","doi-asserted-by":"publisher","DOI":"10.1159\/000448639"},{"key":"2025110505250927000_2025.08.12.669854v3.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-0395-6"},{"key":"2025110505250927000_2025.08.12.669854v3.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.24.1.1041"},{"key":"2025110505250927000_2025.08.12.669854v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.107"},{"key":"2025110505250927000_2025.08.12.669854v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.04.003"},{"key":"2025110505250927000_2025.08.12.669854v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.03.019"},{"key":"2025110505250927000_2025.08.12.669854v3.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2011.01753.x"},{"key":"2025110505250927000_2025.08.12.669854v3.8","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-012-0326-9"},{"key":"2025110505250927000_2025.08.12.669854v3.9","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35969"},{"key":"2025110505250927000_2025.08.12.669854v3.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003823"},{"key":"2025110505250927000_2025.08.12.669854v3.11","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-017-0501-9"},{"key":"2025110505250927000_2025.08.12.669854v3.12","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61035"},{"key":"2025110505250927000_2025.08.12.669854v3.13","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62508"},{"key":"2025110505250927000_2025.08.12.669854v3.14","doi-asserted-by":"crossref","unstructured":"Kshirsagar, A. & Reiner, O. in Neocortical Neurogenesis in Development and Evolution 365\u2013396 (2023).","DOI":"10.1002\/9781119860914.ch18"},{"key":"2025110505250927000_2025.08.12.669854v3.15","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.150.3.681"},{"key":"2025110505250927000_2025.08.12.669854v3.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106610200"},{"key":"2025110505250927000_2025.08.12.669854v3.17","doi-asserted-by":"publisher","DOI":"10.1038\/364717a0"},{"key":"2025110505250927000_2025.08.12.669854v3.18","doi-asserted-by":"crossref","unstructured":"Hoffmann, B. , Zuo, W. , Liu, A. & Morris, N. 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