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, Jian Fu Chen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2612
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Organoids
Microcephaly
Gene encoding
Cilia
Cell proliferation
Ablation
mice
Brain
Cells
Basal Bodies
deletion
Proteins
Stem Cells
mutations
progressions
genes
ablation
brain
coding
depletion

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zhang, Wei ; Yang, Si Lu ; Yang, Mei ; Herrlinger, Stephanie ; Shao, Qiang ; Collar, John L. ; Fierro, Edgar ; Shi, Yanhong ; Liu, Aimin ; Lu, Hui ; Herring, Bruce E. ; Guo, Ming Lei ; Buch, Shilpa ; Zhao, Zhen ; Xu, Jian ; Lu, Zhipeng ; Chen, Jian Fu. / Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
author = "Wei Zhang and Yang, {Si Lu} and Mei Yang and Stephanie Herrlinger and Qiang Shao and Collar, {John L.} and Edgar Fierro and Yanhong Shi and Aimin Liu and Hui Lu and Herring, {Bruce E.} and Guo, {Ming Lei} and Shilpa Buch and Zhen Zhao and Jian Xu and Zhipeng Lu and Chen, {Jian Fu}",
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Zhang, W, Yang, SL, Yang, M, Herrlinger, S, Shao, Q, Collar, JL, Fierro, E, Shi, Y, Liu, A, Lu, H, Herring, BE, Guo, ML, Buch, S, Zhao, Z, Xu, J, Lu, Z & Chen, JF 2019, 'Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors', Nature communications, vol. 10, no. 1, 2612. https://doi.org/10.1038/s41467-019-10497-2

Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors. / Zhang, Wei; Yang, Si Lu; Yang, Mei; Herrlinger, Stephanie; Shao, Qiang; Collar, John L.; Fierro, Edgar; Shi, Yanhong; Liu, Aimin; Lu, Hui; Herring, Bruce E.; Guo, Ming Lei; Buch, Shilpa; Zhao, Zhen; Xu, Jian; Lu, Zhipeng; Chen, Jian Fu.

In: Nature communications, Vol. 10, No. 1, 2612, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - Modeling microcephaly with cerebral organoids reveals a WDR62–CEP170–KIF2A pathway promoting cilium disassembly in neural progenitors

AU - Zhang, Wei

AU - Yang, Si Lu

AU - Yang, Mei

AU - Herrlinger, Stephanie

AU - Shao, Qiang

AU - Collar, John L.

AU - Fierro, Edgar

AU - Shi, Yanhong

AU - Liu, Aimin

AU - Lu, Hui

AU - Herring, Bruce E.

AU - Guo, Ming Lei

AU - Buch, Shilpa

AU - Zhao, Zhen

AU - Xu, Jian

AU - Lu, Zhipeng

AU - Chen, Jian Fu

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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