| MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway. | |
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MedLine Citation:
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PMID: 21947081 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Primary microcephaly 1 is a neurodevelopmental disorder caused by mutations in the MCPH1 gene, whose product MCPH1 (also known as microcephalin and BRIT1) regulates DNA-damage response. Here we show that Mcph1 disruption in mice results in primary microcephaly, mimicking human MCPH1 symptoms, owing to a premature switching of neuroprogenitors from symmetric to asymmetric division. MCPH1-deficiency abrogates the localization of Chk1 to centrosomes, causing premature Cdk1 activation and early mitotic entry, which uncouples mitosis and the centrosome cycle. This misorients the mitotic spindle alignment and shifts the division plane of neuroprogenitors, to bias neurogenic cell fate. Silencing Cdc25b, a centrosome substrate of Chk1, corrects MCPH1-deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1-knockout neocortex. Thus, MCPH1, through its function in the Chk1-Cdc25-Cdk1 pathway to couple the centrosome cycle with mitosis, is required for precise mitotic spindle orientation and thereby regulates the progenitor division mode to maintain brain size. |
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Authors:
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Ralph Gruber; Zhongwei Zhou; Mikhail Sukchev; Tjard Joerss; Pierre-Olivier Frappart; Zhao-Qi Wang |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-25 |
Journal Detail:
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Title: Nature cell biology Volume: - ISSN: 1476-4679 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100890575 Medline TA: Nat Cell Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beurtenbergstrasse 11, 07745 Jena, Germany. |
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