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Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors

Author

Listed:
  • Wei Zhang

    (University of Southern California (USC))

  • Si-Lu Yang

    (University of Georgia)

  • Mei Yang

    (University of Southern California (USC))

  • Stephanie Herrlinger

    (University of Georgia)

  • Qiang Shao

    (University of Southern California (USC))

  • John L. Collar

    (University of Georgia)

  • Edgar Fierro

    (University of Georgia)

  • Yanhong Shi

    (Beckman Research Institute of City of Hope)

  • Aimin Liu

    (The Pennsylvania State University)

  • Hui Lu

    (The George Washington University)

  • Bruce E. Herring

    (University of Southern California)

  • Ming-Lei Guo

    (University of Nebraska Medical Center)

  • Shilpa Buch

    (University of Nebraska Medical Center)

  • Zhen Zhao

    (University of Southern California)

  • Jian Xu

    (University of Southern California (USC))

  • Zhipeng Lu

    (University of Southern California)

  • Jian-Fu Chen

    (University of Southern California (USC))

Abstract

Primary microcephaly is caused by mutations in genes encoding centrosomal proteins including WDR62 and KIF2A. However, mechanisms underlying human microcephaly remain elusive. By creating mutant mice and human cerebral organoids, here we found that WDR62 deletion resulted in a reduction in the size of mouse brains and organoids due to the disruption of neural progenitor cells (NPCs), including outer radial glia (oRG). WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of NPCs. Mechanistically, WDR62 interacts with and promotes CEP170’s localization to the basal body of primary cilium, where CEP170 recruits microtubule-depolymerizing factor KIF2A to disassemble cilium. WDR62 depletion reduced KIF2A’s basal body localization, and enhanced KIF2A expression partially rescued deficits in cilium length and NPC proliferation. Thus, modeling microcephaly with cerebral organoids and mice reveals a WDR62-CEP170-KIF2A pathway promoting cilium disassembly, disruption of which contributes to microcephaly.

Suggested Citation

  • Wei Zhang & Si-Lu Yang & Mei Yang & Stephanie Herrlinger & Qiang Shao & John L. Collar & Edgar Fierro & Yanhong Shi & Aimin Liu & Hui Lu & Bruce E. Herring & Ming-Lei Guo & Shilpa Buch & Zhen Zhao & J, 2019. "Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10497-2
    DOI: 10.1038/s41467-019-10497-2
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    Cited by:

    1. Sarah E. Conduit & Wayne Pearce & Amandeep Bhamra & Benoit Bilanges & Laura Bozal-Basterra & Lazaros C. Foukas & Mathias Cobbaut & Sandra D. Castillo & Mohammad Amin Danesh & Mahreen Adil & Arkaitz Ca, 2024. "A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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