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TALPID3 encoded by <jats:italic>KIAA0856<\/jats:italic> in man (<jats:italic>2700049A03Rik<\/jats:italic> in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in <jats:italic>KIAA0856<\/jats:italic> have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11\u201312 of <jats:italic>Talpid3<\/jats:italic> in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. <jats:italic>Talpid3<\/jats:italic> mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre\u2010derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in <jats:italic>Wnt7a<\/jats:italic> expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of <jats:italic>Talpid3<\/jats:italic>. The <jats:italic>Talpid3<\/jats:italic> conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for <jats:italic>Talpid3<\/jats:italic> in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. \u00a9 2019 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5271","type":"journal-article","created":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T02:20:45Z","timestamp":1553826045000},"page":"396-408","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Mice with a conditional deletion of <i>Talpid3<\/i> (<i>KIAA0586<\/i>)\u00a0\u2013\u00a0a model for Joubert syndrome"],"prefix":"10.1002","volume":"248","author":[{"given":"Andrew L","family":"Bashford","sequence":"first","affiliation":[{"name":"Department of Biology and Biochemistry University of Bath  Bath 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