{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:18:16Z","timestamp":1790759896989,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia Espa\u00f1a","award":["RTI2018-095582-B-I00,RED2018-102723-T,AEI-MICIU CEX2019-000891-S"],"award-info":[{"award-number":["RTI2018-095582-B-I00,RED2018-102723-T,AEI-MICIU CEX2019-000891-S"]}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"crossref","award":["B2017\/BMD-3884"],"award-info":[{"award-number":["B2017\/BMD-3884"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100011102","name":"European Commission Seventh Framework Programme","doi-asserted-by":"crossref","award":["NEURON8-Full-815-094"],"award-info":[{"award-number":["NEURON8-Full-815-094"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Worldwide Cancer Research and the AECC","award":["WCR20-155"],"award-info":[{"award-number":["WCR20-155"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,23]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>MCPH<\/jats:italic>\n                    genes and lack of comparative in vivo studies. By generating a series of CRISPR\/Cas9-mediated genetic KOs, we report here that \u2014 whereas defects in spindle pole proteins (ASPM,\n                    <jats:italic>MCPH5<\/jats:italic>\n                    ) result in mild MCPH during development \u2014 lack of centrosome (CDK5RAP2,\n                    <jats:italic>MCPH3<\/jats:italic>\n                    ) or centriole (CEP135,\n                    <jats:italic>MCPH8<\/jats:italic>\n                    ) 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.\n                    <jats:italic>Trp53<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.146364","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T12:02:03Z","timestamp":1625745723000},"source":"Crossref","is-referenced-by-count":17,"title":["Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3850-6803","authenticated-orcid":true,"given":"Jos\u00e9","family":"Gonz\u00e1lez-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8156-1218","authenticated-orcid":true,"given":"Andrzej W.","family":"Cwetsch","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."},{"name":"Imagine Institute of Genetic Diseases, University of Paris, Paris, France."},{"name":"Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, University of Paris, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Mart\u00ednez-Alonso","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis R.","family":"L\u00f3pez-Sainz","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0652-6447","authenticated-orcid":true,"given":"Jorge","family":"Almagro","sequence":"additional","affiliation":[{"name":"Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Melati","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8567-8907","authenticated-orcid":true,"given":"Jes\u00fas","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-6895","authenticated-orcid":true,"given":"Manuel","family":"P\u00e9rez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-0518","authenticated-orcid":true,"given":"Diego","family":"Meg\u00edas","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Unit and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6135-0686","authenticated-orcid":true,"given":"Jasminka","family":"Boskovic","sequence":"additional","affiliation":[{"name":"Electron Microscopy Unit, CNIO, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Gilabert-Juan","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."},{"name":"University of Paris, NeuroDiderot, Inserm, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osvaldo","family":"Gra\u00f1a-Castro","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, CNIO, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Pierani","sequence":"additional","affiliation":[{"name":"Imagine Institute of Genetic Diseases, University of Paris, Paris, France."},{"name":"Institute of Psychiatry and Neuroscience of Paris, INSERM U-1266, University of Paris, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-1143","authenticated-orcid":true,"given":"Axel","family":"Behrens","sequence":"additional","affiliation":[{"name":"Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom."},{"name":"Faculty of Life Sciences, King\u2019s College London, Guy\u2019s Campus, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1865-7102","authenticated-orcid":true,"given":"Sagrario","family":"Ortega","sequence":"additional","affiliation":[{"name":"Mouse Gene Editing Unit, CNIO, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0829-6315","authenticated-orcid":true,"given":"Marcos","family":"Malumbres","sequence":"additional","affiliation":[{"name":"Cell Division and Cancer group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2021,8,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2011.04.007"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.056"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2009.09.011"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1242\/dev.170613"},{"issue":"6","key":"B5","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nrm2180","article-title":"Centrosome biogenesis and function: centrosomics brings new understanding","volume":"8","author":"Bettencourt-Dias","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.11.042"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1320"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.20.7813-7825.2000"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1220"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200108088"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060224"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2012.06.001"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-11-1115"},{"issue":"pt 23","key":"B14","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.1242\/jcs.113506","article-title":"Drosophila Cep135\/Bld10 maintains proper centriole structure but is dispensable for cartwheel formation","volume":"125","author":"Roque","year":"2012","journal-title":"J Cell Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e13-03-0149"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.56"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.03.016"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61762"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010494107"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.01.002"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1242\/dev.040410"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106474"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.12232"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5692"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-083117-021441"},{"key":"B26","doi-asserted-by":"crossref","DOI":"10.1155\/2014\/547986","article-title":"Molecular and cellular basis of autosomal recessive primary microcephaly","volume":"2014","author":"Barbelanne","year":"2014","journal-title":"Biomed Res Int"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2015.138"},{"issue":"pt 9","key":"B28","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1242\/jcs.064931","article-title":"Stepwise evolution of the centriole-assembly pathway","volume":"123","author":"Carvalho-Santos","year":"2010","journal-title":"J Cell Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3373"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3329"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400568111"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3831"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.01.012"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy350"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8676"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604066103"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201541823"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ng.683"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008200"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1307491"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot090704"},{"issue":"1\u20132","key":"B42","first-page":"70","article-title":"ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays","volume":"347","author":"Hu","year":"2009","journal-title":"J Immunol Methods"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0891-2"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15359-w"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.2174\/1574893612666170810153850"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/146364\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:45:09Z","timestamp":1779147909000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/146364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,23]]},"references-count":47,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8,23]]},"published-print":{"date-parts":[[2021,8,23]]}},"alternative-id":["10.1172\/jci.insight.146364"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.146364","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,23]]},"article-number":"e146364"}}