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Mutations in genes encoding ubiquitously expressed RNA exosome subunits cause selective neurological disease, highlighting a poorly understood role for RNA surveillance in nervous system development. Here, we demonstrate that RNA exosome dysfunction alters the temporal coordination of gene expression during human cerebellar differentiation. Using CRISPR-engineered human cerebellar organoids modeling pathogenic EXOSC3 variants, we show that cerebellar lineages remain specified, but exhibit altered developmental trajectories, cellular composition, and maturation-associated transcriptional programs. Lineage-resolved transcriptomic and regulon analyses reveal selective disruption of developmental regulatory programs, particularly in Purkinje cells. These molecular abnormalities are accompanied by disorganized cerebellar architecture and impaired coordination of spontaneous neuronal activity. Together, our findings identify RNA exosome surveillance as a contributor to the temporal regulation of cerebellar development and support an early neurodevelopmental component of pontocerebellar hypoplasia type 1b pathogenesis.<\/jats:p>","DOI":"10.64898\/2026.04.19.719460","type":"posted-content","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:40:22Z","timestamp":1776854422000},"source":"Crossref","is-referenced-by-count":0,"title":["RNA exosome-mediated RNA surveillance governs developmental timing in the human cerebellum"],"prefix":"10.64898","author":[{"given":"Nina A.","family":"Barr","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozhidar","family":"Baltov","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rylee E.","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jash J.","family":"Gada","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Wade","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan N.","family":"Tjoa","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anoothi","family":"Seth","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4280-9994","authenticated-orcid":false,"given":"Kafui","family":"Dzirasa","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Duke University School of Medicine Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashleigh E.","family":"Schaffer","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics Oregon Health and Science University Portland, OR 97239"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunmin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6070-0904","authenticated-orcid":false,"given":"Derrick J.","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biosciences University of Southern California Los Angeles, CA 90089"},{"name":"Leonard David School of Gerontology University of Southern California Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026102104351383000_2026.04.19.719460v3.1","doi-asserted-by":"publisher","DOI":"10.1007\/s40778-023-00227-2"},{"key":"2026102104351383000_2026.04.19.719460v3.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax2957"},{"key":"2026102104351383000_2026.04.19.719460v3.3","doi-asserted-by":"crossref","unstructured":"Westbrook, E. 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