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.
Highlights
Autosomal recessive primary microcephaly (MCPH) is a congenital brain disorder characterized by a reduction in head circumference linked to a striking decrease in brain volume
Several genes mutated in MCPH patients have been identified so far (MCPH1-25), including genes encoding proteins associated with centriole biology or the mitotic spindle such as ASPM (MCPH5) and WDR62 (MCPH2), the 2 most commonly mutated MCPH genes [1,2,3,4] (Figure 1A)
We examined the effect of lack of CEP135 in cortical neural progenitors (NPs) isolated from E14.5 neocortices and cultured to generate incipient neurospheres
Summary
Autosomal recessive primary microcephaly (MCPH) is a congenital brain disorder characterized by a reduction in head circumference linked to a striking decrease in brain volume (from –3 to –13 SDs) These changes are typically not linked with gross anomalies of brain architecture and associate with a primary and selective defect in the production of neurons during development. Centrioles consist of 9 microtubule triplets organized around a cartwheel from which 9 protein spokes emanate radially, conferring a 9-fold symmetric conformation that stabilizes the structure [5] These structures recruit several proteins to polymerize a robust pericentriolar matrix (PCM), thereby allowing the generation of a bipolar spindle that ensures the correct segregation of chromosomes to both daughter cells, avoiding chromosomal instability. Deregulation of centrosome dynamics typically results in a variety of cell division defects, affecting neural development [4]
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