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Updated: Oct 29, 2025
Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex
Published on: June 4, 2014
Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical
José González-Martínez1, Andrzej W Cwetsch1,2,3, Diego Martínez-Alonso1
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Abstract:
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.
Insights
Congenital microcephaly (MCPH) can stem from centriole defects in neural progenitors. Loss of CEP135 causes instability and cell death, leading to brain malformations if cells aren't cleared.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Congenital microcephaly (MCPH) is a neurodevelopmental disorder linked to gene mutations affecting mitosis.
- The precise cellular mechanisms driving MCPH remain unclear due to genetic diversity and limited in vivo research.
Purpose of the Study:
- To investigate the cellular pathogenesis of MCPH by comparing the effects of different gene knockouts in vivo.
- To elucidate the role of centriole integrity in neural progenitor cells during brain development.
Main Methods:
- CRISPR/Cas9 gene editing to create knockout models for key MCPH-associated genes (ASPM, CDK5RAP2, CEP135).
- Development of a mouse model for MCPH8 (CEP135 deficiency).
- Analysis of neural progenitor cell dynamics, chromosome segregation, TP53 activation, and cell death.
Main Results:
- Defects in spindle pole proteins (ASPM) caused mild MCPH.
- Loss of centrosome (CDK5RAP2) or centriole (CEP135) regulators led to delayed chromosome segregation and instability in neural progenitors.
- CEP135 deficiency resulted in centriole duplication defects, TP53 activation, and neural progenitor cell death.
- Trp53 ablation in Cep135-deficient mice prevented cell death but not microcephaly, causing subcortical heterotopias.
Conclusions:
- Centriole defects in neural progenitors contribute to MCPH pathogenesis.
- Failure to eliminate chromosomally unstable cells due to centriole dysfunction can lead to brain architectural defects.
- TP53-mediated cell death is a critical mechanism for clearing defective cells, but its absence does not prevent microcephaly itself.
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