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dc.contributor.authorGonzález-Martínez, J
dc.contributor.authorCwetsch, AW
dc.contributor.authorMartínez-Alonso, D
dc.contributor.authorLópez-Sainz, LR
dc.contributor.authorAlmagro, J
dc.contributor.authorMelati, A
dc.contributor.authorGómez, J
dc.contributor.authorPérez-Martínez, M
dc.contributor.authorMegías, D
dc.contributor.authorBoskovic, J
dc.contributor.authorGilabert-Juan, J
dc.contributor.authorGraña-Castro, O
dc.contributor.authorPierani, A
dc.contributor.authorBehrens, A
dc.contributor.authorOrtega, S
dc.contributor.authorMalumbres, M
dc.date.accessioned2021-09-23T09:43:53Z
dc.date.available2021-09-23T09:43:53Z
dc.date.issued2021-08-23
dc.identifier.citationJCI insight, 2021, 6 (16)
dc.identifier.issn2379-3708
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4826
dc.identifier.eissn2379-3708
dc.identifier.doi10.1172/jci.insight.146364
dc.description.abstractCongenital 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.
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.publisherAMER SOC CLINICAL INVESTIGATION INC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleDeficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.
dc.typeJournal Article
dcterms.dateAccepted2021-07-07
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1172/jci.insight.146364
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-08-23
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJCI insight
pubs.issue16
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.publication-statusPublished
pubs.volume6
pubs.embargo.termsNot known
dc.contributor.icrauthorBehrens, Axel


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