Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias

JCI Insight. 2021 Aug 23;6(16):e146364. doi: 10.1172/jci.insight.146364.


Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our mouse model of MCPH8 suggests that loss of CEP135 results in centriole duplication defects, TP53 activation, and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death but not MCPH, and it leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that MCPH in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.

Keywords: Cell Biology; Cell cycle; Development; Genetic diseases; Neurodevelopment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / pathology
  • CRISPR-Cas Systems / genetics
  • Calmodulin-Binding Proteins / genetics
  • Calmodulin-Binding Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Centrioles / genetics*
  • Centrioles / pathology
  • Chromosomal Instability*
  • Disease Models, Animal
  • Embryo, Mammalian
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Microscopy, Electron, Transmission
  • Molecular Imaging
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / pathology*
  • Neural Stem Cells / ultrastructure
  • Primary Cell Culture
  • Time-Lapse Imaging
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • ASPM protein, mouse
  • Calmodulin-Binding Proteins
  • Cdk5rap2 protein, mouse
  • Cell Cycle Proteins
  • Nerve Tissue Proteins
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53