title: MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway.
abstract: 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.
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, Beurtenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Gruber
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Zhou
authors.forename: Mikhail
authors.initials: M
authors.lastname: Sukchev
authors.forename: Tjard
authors.initials: T
authors.lastname: Joerss
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Frappart
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018385:Centrosome / Q000201:enzymology*; D000071877:Checkpoint Kinase 1; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008938:Mitosis; D019579:Neocortex / Q000201:enzymology* / Q000473:pathology; D058953:Neural Stem Cells / Q000201:enzymology* / Q000473:pathology; D009929:Organ Size; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000201:enzymology; D014162:Transfection; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C547654:MCPH1 protein, mouse; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C517006:Cdc25b protein, mouse; D020687:cdc25 Phosphatases