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In this paper, we developed an <jats:italic>in vitro<\/jats:italic> neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (<jats:italic>AHI1, CPLANE1<\/jats:italic>, <jats:italic>TMEM67<\/jats:italic>, and <jats:italic>CC2D2A<\/jats:italic>) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31\u00a0days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant <jats:italic>in vitro<\/jats:italic> model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.<\/jats:p>","DOI":"10.1007\/s00441-024-03876-9","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T06:51:21Z","timestamp":1710831081000},"page":"255-267","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro"],"prefix":"10.1007","volume":"396","author":[{"given":"Roberta","family":"De Mori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Tardivo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Pollara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Clara","family":"Giliani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eltahir","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Fischetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Gener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santo","family":"Diprima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco J.","family":"Morelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-5738","authenticated-orcid":false,"given":"Virginie","family":"Sottile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6820","authenticated-orcid":false,"given":"Enza Maria","family":"Valente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"3876_CR1","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1242\/dmm.019083","volume":"8","author":"ZA Abdelhamed","year":"2015","unstructured":"Abdelhamed ZA, Natarajan S, Wheway G, Inglehearn CF, Toomes C, Johnson CA, Jagger DJ (2015) The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway. 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