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Lack of adaptation to centriolar defects leads to p53-independent microcephaly in the absence of Cep135

José González-Martínez, Andrzej W Cwetsch, Diego Martínez-Alonso, Luis Rodrigo López-Sainz, View ORCID ProfileJorge Almagro, Diego Megías, Jasminka Boskovic, Javier Gilabert-Juan, Osvaldo Graña-Castro, Alessandra Pierani, View ORCID ProfileAxel Behrens, Sagrario Ortega, View ORCID ProfileMarcos Malumbres
doi: https://doi.org/10.1101/2020.05.07.082032
José González-Martínez
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Andrzej W Cwetsch
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
2Imagine Institute of Genetic Diseases, Université de Paris, Paris 75015, France
3Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, Université de Paris, Paris 75014, France
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Diego Martínez-Alonso
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Luis Rodrigo López-Sainz
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Jorge Almagro
4Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
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  • ORCID record for Jorge Almagro
Diego Megías
5Confocal Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Jasminka Boskovic
6Electron Microscopy Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Javier Gilabert-Juan
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
7Université de Paris, NeuroDiderot, Inserm, F-75019 Paris, France
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Osvaldo Graña-Castro
8Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Alessandra Pierani
2Imagine Institute of Genetic Diseases, Université de Paris, Paris 75015, France
3Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, Université de Paris, Paris 75014, France
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Axel Behrens
4Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK
9Faculty of Life Sciences, King’s College London, Guy’s Campus, London, SE1 1UL, UK
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Sagrario Ortega
10Mouse Gene Editing Unit, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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Marcos Malumbres
1Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain
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  • ORCID record for Marcos Malumbres
  • For correspondence: malumbres@cnio.es
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Abstract

Autosomal Recessive Primary Microcephaly (MCPH) is a rare disease associated to proteins involved in centrosomal and spindle dynamics including Cep135 (MCPH8). Although Cep135 has been associated to centriolar assembly, the mechanisms associated to the pathogenesis underlying MCPH8 mutations are unclear. By using a series of CRISPR/Cas9-edited murine Cep135 alleles, we report here that lack of Cep135 results in perinatal lethality accompanied by significant microcephaly in a dosis-dependent manner. Cep135 deficiency, but not that of other centrosomal microcephaly proteins such as Aspm or Cdk5rap2, induces centrosome duplication defects, and perturbed centriole structure and dynamics. Whereas other cell types are able to quickly adapt to these defects, neural progenitors display a prolonged response leading to chromosomal instability and cell death in later developmental stages. Genetic ablation of Trp53 in these mutant embryos prevents apoptotic cell death but does not rescue the microcephaly induced by Cep135 loss. These results suggest that microcephaly can arise from the lack of adaptation to centriole defects in neural progenitors of the developing neocortex in a p53-independent manner.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

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  • https://malumbreslab.org

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Lack of adaptation to centriolar defects leads to p53-independent microcephaly in the absence of Cep135
José González-Martínez, Andrzej W Cwetsch, Diego Martínez-Alonso, Luis Rodrigo López-Sainz, Jorge Almagro, Diego Megías, Jasminka Boskovic, Javier Gilabert-Juan, Osvaldo Graña-Castro, Alessandra Pierani, Axel Behrens, Sagrario Ortega, Marcos Malumbres
bioRxiv 2020.05.07.082032; doi: https://doi.org/10.1101/2020.05.07.082032
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Lack of adaptation to centriolar defects leads to p53-independent microcephaly in the absence of Cep135
José González-Martínez, Andrzej W Cwetsch, Diego Martínez-Alonso, Luis Rodrigo López-Sainz, Jorge Almagro, Diego Megías, Jasminka Boskovic, Javier Gilabert-Juan, Osvaldo Graña-Castro, Alessandra Pierani, Axel Behrens, Sagrario Ortega, Marcos Malumbres
bioRxiv 2020.05.07.082032; doi: https://doi.org/10.1101/2020.05.07.082032

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