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

Nat Commun. 2019 Jun 13;10(1):2612. doi: 10.1038/s41467-019-10497-2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Cilia / metabolism
  • Disease Models, Animal
  • Female
  • Gene Knockout Techniques
  • Humans
  • Kinesins / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Microcephaly / genetics
  • Microcephaly / pathology*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / pathology
  • Neuroglia / cytology
  • Neuroglia / pathology
  • Organoids / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / metabolism*


  • Cell Cycle Proteins
  • Cep170 protein, human
  • Cep170 protein, mouse
  • KIF2A protein, human
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Repressor Proteins
  • WDR62 protein, human
  • WDR62 protein, mouse
  • KIF2A protein, mouse
  • Kinesins