title: Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate.
abstract: Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm (abnormal spindle-like, microcephaly-associated) and Wdr62 (WD repeat-containing protein 62) interact genetically to control brain size, with mice lacking Wdr62, Aspm, or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links among centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Jayaraman
authors.affiliation: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kodani
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Dilenny M
authors.initials: DM
authors.lastname: Gonzalez
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Mancias
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Vagnoni
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Nevan
authors.initials: N
authors.lastname: Krogan
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.affiliation: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA. Electronic address: timothy.yu@childrens.harvard.edu.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: byoung-il.bae@yale.edu.
authors.forename: Byoung-Il
authors.initials: BI
authors.lastname: Bae
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology* / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002502:Centrioles / Q000378:metabolism*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D000066450:Mouse Embryonic Stem Cells; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D001678:Organelle Biogenesis
chemical_list: C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D018797:Cell Cycle Proteins; C580968:Cenpj protein, mouse; C586106:Cep63 protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C581545:WDR62 protein, mouse
keywords: Aspm; Wdr62; apical complex; maternal centriole