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

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, Jian Xu, Zhipeng Lu and Jian-Fu Chen ()
Additional contact information
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)

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10497-2

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