title: mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis.
abstract: Radial glial cells (RCGs) are self-renewing progenitor cells that give rise to neurons and glia during embryonic development. Throughout neurogenesis, these cells contact the cerebral ventricles and bear a primary cilium. Although the role of the primary cilium in embryonic patterning has been studied, its role in brain ventricular morphogenesis is poorly characterized. Using conditional mutants, we show that the primary cilia of radial glia determine the size of the surface of their ventricular apical domain through regulation of the mTORC1 pathway. In cilium-less mutants, the orientation of the mitotic spindle in radial glia is also significantly perturbed and associated with an increased number of basal progenitors. The enlarged apical domain of RGCs leads to dilatation of the brain ventricles during late embryonic stages (ventriculomegaly), which initiates hydrocephalus during postnatal stages. These phenotypes can all be significantly rescued by treatment with the mTORC1 inhibitor rapamycin. These results suggest that primary cilia regulate ventricle morphogenesis by acting as a brake on the mTORC1 pathway. This opens new avenues for the diagnosis and treatment of hydrocephalus.
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Foerster
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Daclin
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France.
authors.forename: Shihavuddin
authors.initials: S
authors.lastname: Asm
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Faucourt
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boletta
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France.
authors.forename: Auguste
authors.initials: A
authors.lastname: Genovesio
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), INSERM U1024, and CNRS UMR 8197, PSL Research University, 46 rue d'Ulm, Paris 75005, France nathalie.spassky@ens.fr.
authors.forename: Nathalie
authors.identifier: 0000-0003-4722-6464
authors.initials: N
authors.lastname: Spassky
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology; D016764:Cell Polarity / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D002923:Cilia / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
chemical_list: D046912:Multiprotein Complexes; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Cilia; Hydrocephalus; Ventricular system; mTORC1 pathway