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Neuron. 2016 Nov 23;92(4):813-828. doi: 10.1016/j.neuron.2016.09.056. Epub 2016 Oct 27.

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate.

Author information

1
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.
2
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
3
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.
4
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.
5
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.
6
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
7
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
9
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.
10
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.
11
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.

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.

KEYWORDS:

Aspm; Wdr62; apical complex; maternal centriole

PMID:
27974163
PMCID:
PMC5199216
DOI:
10.1016/j.neuron.2016.09.056
[Indexed for MEDLINE]
Free PMC Article

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