title: Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool.
abstract: Cerebellar granule cell precursors (GCPs), which give rise to the most abundant neuronal type in the mammalian brain, arise from a restricted pool of primary progenitors in the rhombic lip (RL). Sonic hedgehog (Shh) secreted by developing Purkinje cells is essential for the expansion of GCPs and for cerebellar morphogenesis. Recent studies have shown that the primary cilium concentrates components of Shh signaling and that this structure is required for Shh signaling. GCPs have a primary cilium on their surface [Del Cerro, M.P., Snider, R.S. (1972). Studies on the developing cerebellum. II. The ultrastructure of the external granular layer. J Comp Neurol 144, 131-64.]. Here, we show that 1) this cilium can be conditionally ablated by crossing Kif3a(fl/-) mice with hGFAP-Cre mice, 2) removal of Kif3a from GCPs disrupts cerebellar development, and 3) these defects are due to a drastic reduction in Shh-dependent expansion of GCPs. A similar phenotype is observed when Smoothened (Smo), an essential transducer of Shh signaling, is removed from the same population of GCPs. Interestingly, Kif3a-Smo double conditional mutants show that Kif3a is epistatic to Smo. This work shows that Kif3a is essential for Shh-dependent expansion of cerebellar progenitors. Dysfunctional cilia are associated with diverse human disorders including Bardet-Biedl and Joubert syndromes. Cerebellar abnormalities observed in these patients could be explained by defects in Shh-induced GCP expansion.
authors: Université Pierre and Marie Curie, IFR des Neurosciences, INSERM U711, Hôpital Pitié-Salpêtrière, Paris, F-75013, France. spassky@ccr.jussieu.fr
authors: N
authors: N
authors: Spassky
authors: Y-G
authors: YG
authors: Han
authors: A
authors: A
authors: Aguilar
authors: L
authors: L
authors: Strehl
authors: L
authors: L
authors: Besse
authors: C
authors: C
authors: Laclef
authors: M Romaguera
authors: MR
authors: Ros
authors: J M
authors: JM
authors: Garcia-Verdugo
authors: A
authors: A
authors: Alvarez-Buylla
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology* / Q000196:embryology; D002923:Cilia / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011689:Purkinje Cells / Q000166:cytology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000166:cytology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D016547:Kinesins