title: Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size.
abstract: Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly.
authors.affiliation: 1] Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado 80045, USA [2] Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: Jian-Fu
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado 80045, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado 80045, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilde
authors.affiliation: Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Lai
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado 80045, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000378:metabolism*; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D051379:Mice; D008831:Microcephaly / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008938:Mitosis / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins; D058953:Neural Stem Cells / Q000378:metabolism*; D009929:Organ Size; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C581545:WDR62 protein, mouse; C576918:Aurka protein, mouse; D064096:Aurora Kinase A