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Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size

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  • Jian-Fu Chen

    (Howard Hughes Medical Institute, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado
    University of Georgia)

  • Ying Zhang

    (Howard Hughes Medical Institute, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado)

  • Jonathan Wilde

    (Howard Hughes Medical Institute, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado)

  • Kirk C. Hansen

    (Biochemistry & Molecular Genetics, University of Colorado Denver)

  • Fan Lai

    (The Wistar Institute)

  • Lee Niswander

    (Howard Hughes Medical Institute, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado)

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.

Suggested Citation

  • Jian-Fu Chen & Ying Zhang & Jonathan Wilde & Kirk C. Hansen & Fan Lai & Lee Niswander, 2014. "Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4885
    DOI: 10.1038/ncomms4885
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    Cited by:

    1. Giulia Fasano & Valentina Muto & Francesca Clementina Radio & Martina Venditti & Niloufar Mosaddeghzadeh & Simona Coppola & Graziamaria Paradisi & Erika Zara & Farhad Bazgir & Alban Ziegler & Giovanni, 2022. "Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish," Nature Communications, Nature, vol. 13(1), pages 1-29, December.

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