Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias
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 compar...
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| Published in | JCI insight Vol. 6; no. 16 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
23.08.2021
American Society for Clinical investigation |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2379-3708 2379-3708 |
| DOI | 10.1172/jci.insight.146364 |
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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. |
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| AbstractList | 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. 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. 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.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. |
| Author | Gilabert-Juan, Javier Martínez-Alonso, Diego Boskovic, Jasminka Almagro, Jorge Pérez-Martínez, Manuel Behrens, Axel Cwetsch, Andrzej W. Graña-Castro, Osvaldo López-Sainz, Luis R. Megías, Diego González-Martínez, José Melati, Anna Gómez, Jesús Malumbres, Marcos Pierani, Alessandra Ortega, Sagrario |
| AuthorAffiliation | 5 Confocal Microscopy Unit and 1 Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 8 Bioinformatics Unit, CNIO, Madrid, Spain 10 Mouse Gene Editing Unit, CNIO, Madrid, Spain 2 Imagine Institute of Genetic Diseases, University of Paris, Paris, France 4 Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom 6 Electron Microscopy Unit, CNIO, Madrid, Spain 9 Faculty of Life Sciences, King’s College London, Guy’s Campus, London, United Kingdom 3 Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, University of Paris, Paris, France 7 University of Paris, NeuroDiderot, Inserm, Paris, France |
| AuthorAffiliation_xml | – name: 10 Mouse Gene Editing Unit, CNIO, Madrid, Spain – name: 1 Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain – name: 2 Imagine Institute of Genetic Diseases, University of Paris, Paris, France – name: 5 Confocal Microscopy Unit and – name: 8 Bioinformatics Unit, CNIO, Madrid, Spain – name: 7 University of Paris, NeuroDiderot, Inserm, Paris, France – name: 9 Faculty of Life Sciences, King’s College London, Guy’s Campus, London, United Kingdom – name: 3 Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, University of Paris, Paris, France – name: 6 Electron Microscopy Unit, CNIO, Madrid, Spain – name: 4 Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom |
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| Snippet | Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal... |
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| SubjectTerms | Animals Biochemistry, Molecular Biology Brain - cytology Brain - pathology Calmodulin-Binding Proteins - genetics Calmodulin-Binding Proteins - metabolism Cell biology Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Centrioles - genetics Centrioles - pathology Chromosomal Instability CRISPR-Cas Systems - genetics Development Development Biology Disease Models, Animal Embryo, Mammalian Embryology and Organogenesis Female Genomics Humans Life Sciences Male Mice Mice, Knockout Microcephaly - genetics Microcephaly - pathology Microscopy, Electron, Transmission Molecular Imaging Mutation Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neural Stem Cells - cytology Neural Stem Cells - pathology Neural Stem Cells - ultrastructure Neurobiology Neurons and Cognition Primary Cell Culture Time-Lapse Imaging Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| Title | Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias |
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