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

Year: 2019
Type: article
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.
DOI: 10.1038/s41467-019-10497-2
Authors: 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, Jian-Fu Chen
Institutions: University of Southern California, University of Georgia, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Pennsylvania State University, George Washington University, University of Nebraska Medical Center
Language: English
Subfield: Genetics
Open Access status: gold
Estimated APC paid: $5,200
Funders: U.S. Department of Health and Human Services, University of Southern California, National Institutes of Health, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Dental and Craniofacial Research
Awards: mRNA Translation Dysregulation in Neurodevelopmental and Neurodegenerative Diseases (Stephanie Herrlinger), G2291199618, Correlating physiology and transcription during learning in a model for the 22q11.2 deletion, Genetic analysis of a microRNA pathway regulating neural tube closure, Methylation signaling in periodontal health and disease, Mechanisms regulating neural progenitor expansion in the developing brain, G6490713460, G7411236662, Zika Virus Capsid Protein Mediated Blockage of host microRNA machinery, G8718567843
OpenAlex ID: W2950534331
FWCI: 11.84
Cites: 50
Cited by: 196
Related to: 10