title: Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome.
abstract: Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure, F-75005 Paris, France. aguilara@stanford.edu
authors.forename: Andrea
authors.initials: A
authors.lastname: Aguilar
authors.forename: Alice
authors.initials: A
authors.lastname: Meunier
authors.forename: Laetitia
authors.initials: L
authors.lastname: Strehl
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonniere
authors.forename: Tania
authors.initials: T
authors.lastname: Attie-Bitach
authors.forename: Féréchté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Spassky
mesh_terms: D000015:Abnormalities, Multiple; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002526:Cerebellar Diseases / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology / Q000002:abnormalities; D002925:Ciliary Motility Disorders / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins; D004677:Encephalocele / Q000378:metabolism* / Q000473:pathology; D005124:Eye Abnormalities / Q000378:metabolism* / Q000473:pathology; D042381:Granulocyte Precursor Cells / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D052177:Kidney Diseases, Cystic / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012160:Retina / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; C465570:Shh protein, mouse