{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T08:06:58Z","timestamp":1780042018583,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,26]]},"group-title":"Cancer Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Granule cell precursors (GCPs) drive the major postnatal expansion of the cerebellum and are the cells of origin of sonic hedgehog medulloblastoma (SHH MB). Although GCPs are often treated as a uniform population, increasing evidence suggests they are heterogeneous, and whether specific subpopulations show distinct tumorigenic competence remains unclear. Here, we identified a rare Nestin-expressing GCP subpopulation in the normal early postnatal cerebellum and showed that it is spatially restricted, molecularly distinct and highly competent to form tumors. These cells are enriched in the posterior external granule layer and co-express\n                  <jats:italic>Atoh1<\/jats:italic>\n                  . Using different SHH MB mouse models, we showed that when this rare subpopulation of GCPs is targeted they can give rise to SHH MB with an efficiency comparable to targeting a larger number of\n                  <jats:italic>Atoh1<\/jats:italic>\n                  -expressing GCPs and that tumors derived from Nestin-expressing GCPs arise in the posterior-lateral cerebellum. Single cell RNA sequencing revealed that Nestin-expressing GCP have a transcriptome indicating reduced neuronal differentiation and enrichment for stem cell genes compared to bulk GCPs and more closely align with SHH MB cells. Together, our findings reveal functionally important heterogeneity within the GCP lineage and suggest that SHH MB arises preferentially from a small subpopulation of GCPs that express Nestin.\n                <\/jats:p>","DOI":"10.64898\/2026.05.26.727818","type":"posted-content","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T05:05:15Z","timestamp":1779858315000},"source":"Crossref","is-referenced-by-count":0,"title":["A Rare Nestin-Expressing Granule Cell Precursor Subpopulation Underlies SHH Medulloblastoma Formation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7015-0907","authenticated-orcid":false,"given":"Salsabiel","family":"El Nagar","sequence":"first","affiliation":[{"name":"Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA"},{"name":"MangroveNeuro, Biolabs@NYULangone, 45-18 Ct Square W, 6th Fl Long Island City, NY, 11101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinwen","family":"Liang","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA"},{"name":"Capital Medical University and Chinese Institutes for Medical Research, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"Stephen","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Synphen H.","family":"Wu","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA"},{"name":"Department of Neurology, Westchester Medical Center, Valhalla, NY 10595"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7090-9605","authenticated-orcid":false,"given":"Alexandra L.","family":"Joyner","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York 10065, NY, USA"},{"name":"Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York 10021, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052900550447000_2026.05.26.727818v1.1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02727"},{"key":"2026052900550447000_2026.05.26.727818v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abj1598"},{"key":"2026052900550447000_2026.05.26.727818v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.08.001"},{"key":"2026052900550447000_2026.05.26.727818v1.4","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1740936"},{"key":"2026052900550447000_2026.05.26.727818v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2020.611841"},{"key":"2026052900550447000_2026.05.26.727818v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.035"},{"key":"2026052900550447000_2026.05.26.727818v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/srep30337"},{"key":"2026052900550447000_2026.05.26.727818v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-018-0070-6"},{"key":"2026052900550447000_2026.05.26.727818v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601992103"},{"key":"2026052900550447000_2026.05.26.727818v1.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5157-07.2008"},{"key":"2026052900550447000_2026.05.26.727818v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-0961-0"},{"key":"2026052900550447000_2026.05.26.727818v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl9156"},{"key":"2026052900550447000_2026.05.26.727818v1.13","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.108190"},{"key":"2026052900550447000_2026.05.26.727818v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.07.004"},{"key":"2026052900550447000_2026.05.26.727818v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3553"},{"key":"2026052900550447000_2026.05.26.727818v1.16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1547"},{"key":"2026052900550447000_2026.05.26.727818v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.08.028"},{"key":"2026052900550447000_2026.05.26.727818v1.18","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-0657"},{"key":"2026052900550447000_2026.05.26.727818v1.19","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.8.994"},{"key":"2026052900550447000_2026.05.26.727818v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2004.02.008"},{"key":"2026052900550447000_2026.05.26.727818v1.21","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.102515"},{"key":"2026052900550447000_2026.05.26.727818v1.22","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A3990"},{"key":"2026052900550447000_2026.05.26.727818v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.10.023"},{"key":"2026052900550447000_2026.05.26.727818v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-380916-2.00008-5"},{"key":"2026052900550447000_2026.05.26.727818v1.25","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07051"},{"key":"2026052900550447000_2026.05.26.727818v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107831"},{"key":"2026052900550447000_2026.05.26.727818v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.07.005"},{"key":"2026052900550447000_2026.05.26.727818v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.03.075"},{"key":"2026052900550447000_2026.05.26.727818v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05208-9"},{"key":"2026052900550447000_2026.05.26.727818v1.30","doi-asserted-by":"publisher","DOI":"10.1186\/1749-8104-2-26"},{"key":"2026052900550447000_2026.05.26.727818v1.31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717815115"},{"key":"2026052900550447000_2026.05.26.727818v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24511"},{"key":"2026052900550447000_2026.05.26.727818v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1158-7"},{"key":"2026052900550447000_2026.05.26.727818v1.34","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1271-5"},{"key":"2026052900550447000_2026.05.26.727818v1.35","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.20.4395"},{"key":"2026052900550447000_2026.05.26.727818v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4621"},{"key":"2026052900550447000_2026.05.26.727818v1.37","doi-asserted-by":"publisher","DOI":"10.1186\/s13064-019-0128-y"},{"key":"2026052900550447000_2026.05.26.727818v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.07.003"},{"key":"2026052900550447000_2026.05.26.727818v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2017.04.020"},{"key":"2026052900550447000_2026.05.26.727818v1.40","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-017-2581-y"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.26.727818","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T07:55:13Z","timestamp":1780041313000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.26.727818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":40,"URL":"https:\/\/doi.org\/10.64898\/2026.05.26.727818","relation":{},"subject":[],"published":{"date-parts":[[2026,5,26]]},"subtype":"preprint"}}