MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway
| Autor: | Zhao-Qi Wang, Ralph Gruber, Zhong-Wei Zhou, Tjard Joerss, Mikhail Sukchev, Pierre Olivier Frappart |
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| Rok vydání: | 2011 |
| Předmět: |
Microcephaly
Cdc25 Chromosomal Proteins Non-Histone Mitosis Cell Cycle Proteins Neocortex Spindle Apparatus Transfection Mice Neural Stem Cells medicine Animals cdc25 Phosphatases Centrosome duplication Cells Cultured Cell Proliferation Centrosome Mice Knockout biology Cell Differentiation Cell Biology Organ Size medicine.disease Neural stem cell Cell biology Coupling (electronics) Cytoskeletal Proteins Checkpoint Kinase 1 biology.protein RNA Interference Neural development Protein Kinases Signal Transduction |
| Zdroj: | Nature cell biology. 13(11) |
| ISSN: | 1476-4679 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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