title: The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.
abstract: Agenesis of the corpus callosum (AgCC) is a frequent brain disorder found in over 80 human congenital syndromes including ciliopathies. Here, we report a severe AgCC in Ftm/Rpgrip1l knockout mouse, which provides a valuable model for Meckel-Grüber syndrome. Rpgrip1l encodes a protein of the ciliary transition zone, which is essential for ciliogenesis in several cell types in mouse including neuroepithelial cells in the developing forebrain. We show that AgCC in Rpgrip1l(-/-) mouse is associated with a disturbed location of guidepost cells in the dorsomedial telencephalon. This mislocalization results from early patterning defects and abnormal cortico-septal boundary (CSB) formation in the medial telencephalon. We demonstrate that all these defects primarily result from altered GLI3 processing. Indeed, AgCC, together with patterning defects and mispositioning of guidepost cells, is rescued by overexpressing in Rpgrip1l(-/-) embryos, the short repressor form of the GLI3 transcription factor (GLI3R), provided by the Gli3(Δ699) allele. Furthermore, Gli3(Δ699) also rescues AgCC in Rfx3(-/-) embryos deficient for the ciliogenic RFX3 transcription factor that regulates the expression of several ciliary genes. These data demonstrate that GLI3 processing is a major outcome of primary cilia function in dorsal telencephalon morphogenesis. Rescuing CC formation in two independent ciliary mutants by GLI3(Δ699) highlights the crucial role of primary cilia in maintaining the proper level of GLI3R required for morphogenesis of the CC.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and christine.laclef@upmc.fr sylvie.schneider-maunoury@upmc.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Laclef
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Anselme
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Besse
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and Fédération de Neurologie, Groupe hospitalier Pitié-Salpêtrière-APHP, F-75013 Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Catala
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Palmyre
authors.affiliation: Université Claude Bernard Lyon 1 and CNRS, CGPhiMC-UMR5534, F-69622 Villeurbanne, France and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baas
authors.affiliation: Université Claude Bernard Lyon 1 and CNRS, CGPhiMC-UMR5534, F-69622 Villeurbanne, France and.
authors.forename: Marie
authors.initials: M
authors.lastname: Paschaki
authors.affiliation: Institut du Fer à Moulin, INSERM S839, F-75005 Paris, France, Sorbonne Université, UPMC Univ Paris 06, S839, Paris, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Pedraza
authors.affiliation: Institut du Fer à Moulin, INSERM S839, F-75005 Paris, France, Sorbonne Université, UPMC Univ Paris 06, S839, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Métin
authors.affiliation: Université Claude Bernard Lyon 1 and CNRS, CGPhiMC-UMR5534, F-69622 Villeurbanne, France and.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Durand
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, ERL1156 and christine.laclef@upmc.fr sylvie.schneider-maunoury@upmc.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Schneider-Maunoury
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D061085:Agenesis of Corpus Callosum / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002923:Cilia / Q000378:metabolism*; D002925:Ciliary Motility Disorders / Q000235:genetics / Q000378:metabolism; D003337:Corpus Callosum / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004677:Encephalocele / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019579:Neocortex / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012174:Retinitis Pigmentosa; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000074290:Zinc Finger Protein Gli3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C523257:Ftm protein, mouse; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C000605540:RFX3 protein, human; D000071701:Regulatory Factor X Transcription Factors; C000605541:Rfx3 protein, mouse; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3