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Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias
José González-Martínez, … , Sagrario Ortega, Marcos Malumbres
José González-Martínez, … , Sagrario Ortega, Marcos Malumbres
Published July 8, 2021
Citation Information: JCI Insight. 2021;6(16):e146364. https://doi.org/10.1172/jci.insight.146364.
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Research Article Cell biology Development

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

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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.

Authors

José 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

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Figure 5

Cep135 deficiency induces TP53-dependent apoptosis in neural progenitors.

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Cep135 deficiency induces TP53-dependent apoptosis in neural progenitors...
(A) Bright-field macroscopic (left) and H&E staining (middle) images of E11.5 Cep135(+/+) and Cep135(Δ8/Δ8) mouse embryos. IHC staining for TP53 and active caspase 3 (AC3) in the same samples including insets at higher magnification (TP53, left; AC3, right) from the specific areas (forebrain [upper], medullary hindbrain [middle], and liver [bottom]). The quantification of TP53+ and AC3+ cells in brain and rest of the body of Cep135-mutant and control embryos is shown in the right histograms. Scale bars: 1 mm (whole embryo sections) and 10 μm (insets). (B) Bright-field macroscopic images (left), IHC staining (middle), and quantification (right) of TP53+ and AC3+ cells in brain and rest of the body of E14.5 Cep135-mutant and control embryos. Scale bars: 1 mm (whole embryo sections), 100 μm (lower microscopic insets). Representative positive cells are indicated by arrows. (C) Whole-mount 3D immunofluorescence of E14.5 Cep135(+/+), Cep135(Δ278/Δ278), and Cep135(Δ8/Δ8) mouse embryos stained for AC3 (green). Gray color depicts tissue autofluorescence in the 488 channel. Scale bars: 1 mm (whole embryos) and 200 μm (lower microscopic insets). Nctx, neocortex; vs, ventricular surface. Note that green, unspecific positive signal in the vs of Cep135(+/+) samples corresponds to secondary antibody aggregates. (D) Immunostaining for AC3, SOX2, and TUJ1 in 14.5 neocortex from Cep135-null and control mice. Scale bars: 250 μm (left) and 100 μm (right). The bottom histogram shows the quantification of AC3+ cells in these samples. (E) Whole-mount 3D immunofluorescence of E14.5 Cdk5rap2(–/–) mouse embryos stained for AC3 (green). Scale bars: 200 μm. In A, B, and D, data are mean SEM from 3 different embryos; **P < 0.01; ***P < 0.001 by Student’s t test.

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