Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopiasMore about Open Access at the Crick
Authors listJosé González-Martínez Andrzej W Cwetsch Diego Martínez-Alonso Luis R López-Sainz Jorge Almagro Anna Melati Jesús Gómez Manuel Pérez-Martínez Diego Megías Jasminka Boskovic Javier Gilabert-Juan Osvaldo Graña Castro Alessandra Pierani Axel Behrens Sagrario Ortega Marcos Malumbres
Congenital microcephaly (MCPH) is a neurodevelopmental disease associated to 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 knockouts we report here that, whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild microcephaly during development, lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our novel mouse model of MCPH8 suggests that Cep135 deficiency results in centriole duplication, TP53 activation and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death, but not microcephaly, and leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that microcephaly 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.
Journal JCI insight
Issue number 16