{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:09:56Z","timestamp":1778479796558,"version":"3.51.4"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in the PTEN gene have been implicated in autism spectrum disorders (ASD), particularly among individuals with comorbid macrocephaly. In our previous study, we demonstrated that the PTEN p.Ile135Leu variant, in an ASD-related genetic background dependent fashion, disrupts both cortical neurogenesis and gliogenesis. While abnormal cerebellar development is a recognized feature of ASD, the specific cellular targets and timing of disruptions during cerebellar differentiation and development remain poorly understood. To investigate these aspects, we applied our previously established cerebellar organoid protocol and used isogenic human iPSC lines harboring this PTEN-variant. We examined the expression of Purkinje cells, granule cells, interneurons, and glial cells prior to 22\u00a0weeks of differentiation, assessed genes expression at 8\u00a0weeks, and evaluated spontaneous spikes activity in Purkinje cells after 11\u00a0weeks. We observed that cell-type-specific expression patterns differed between the PTEN p.Ile135Leu variant in control versus ASD-genetic backgrounds. However, these background differences were diminished in PTEN knockout lines across both backgrounds. Our single-cell RNA sequencing (scRNA-seq) dataset revealed that the PTEN p.Ile135Leu variant increased the number of interneuron progenitor cells, whereas PTEN knockout led to an expansion of meningeal-like cells in both genetic contexts. Moreover, both the PTEN p.Ile135Leu variant and PTEN knockout abolished spontaneous simple spikes activity in Purkinje cells across both backgrounds, including PTEN-corrected patient-derived lines. Together, these findings provide direct evidence linking PTEN dysfunction and genetic background to altered cerebellar differentiation and neuronal network activity in human cerebellar organoids.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf185","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T12:59:26Z","timestamp":1764075566000},"source":"Crossref","is-referenced-by-count":1,"title":["PTEN variant and genetic backgrounds combine to modify cerebellar neuronal differentiation in autism spectrum disorder"],"prefix":"10.1093","volume":"35","author":[{"given":"Ya","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Genetics and Genome Sciences, CWRU School of Medicine , 10900 Euclid Ave., BRB721, Cleveland, OH 44106, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Sciences, CWRU School of Medicine , 10900 Euclid Ave., BRB721, Cleveland, OH 44106, United States"},{"name":"Genomic Analysis Laboratory, The Salk Institute for Biological Studies , 10010 North Torrey Pines Road, La Jolla, CA 92037,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy P H","family":"Sit","sequence":"additional","affiliation":[{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge , 7 Downing Place, Cambridge , CB2 3DY,","place":["United Kingdom"]},{"name":"Sainsbury Wellcome Centre, University College London , 25 Howland St. London , W1T 4JG,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2780-1540","authenticated-orcid":false,"given":"Anthony","family":"Wynshaw-Boris","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Sciences, CWRU School of Medicine , 10900 Euclid Ave., BRB721, Cleveland, OH 44106, United 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