论文部分内容阅读
Primary microcephaly 1 (MCPH1;OMIM251200) is an autosomal recessive neurodevelopmental disorder characterized by a very small brain (microcephaly), which is regarded as a evolution regression of the brain enlargement in mammals.MCPH1 has been shown to encode a centrosome component, but also to form nuclear foci after ionizing and UV irradiation, which colocalise with 53BP1, MDC1, NBS1, ATM, RPA, and ATR.Molecular studies indicated that MCPH1 regulates the ATM-and ATR-mediated DNA damage response and cell cycle progression.These seemingly unrelated phenotypes argue for function complexities of the MCPH1 gene in vivo.To study the function of MCPHI in neurogenesis, we disrupted the Mcph1 gene in mice.MCPH1 deletion in mice results in primary microcephaly, mimicking human MCPH 1 symptoms, due to a premature switching of neuronprogenitors from a symmetric to an asymmetric division.MCPHl-deficiency abrogates the Chkl localization to centrosomes, causing a 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, which bias neurogenic cell fate.Intriguingly, silencing Cdc25b, a centrosome substrate of Chkl, corrects MCPH1 deficiency-induced spindle misalignment and rescues the premature neurogenic production in Mcph1 knockout neocortex.Thus, MCPH1, via its function in the regulation of the Chkl-Cdc25-Cdkl pathway, is required for precise mitotic spindle orientation and thereby modulates the neuroprogenitor division mode to maintain brain size.