Function of MCPH1 in Neurogenesis

Abstract

Primary Microcephaly (MCPH), an autosomal recessive disorder, is characterized by a reduction of the brain size in particular the cerebral cortex size. MCPH can be caused by mutations in any of seven MCPH loci: Microcephalin, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ and STIL. All of the MCPH gene products have been shown to associate with the centrosomes either throughout the cell cycle or specific during mitosis. MCPH1, encoded by Microcephalin, has been shown to function in the DNA damage response and chromosome condensation. However, the role of MCPH1 in determining the mammalian brain size is not known. Aim of the study was to identify the function of MCPH1 in the development of the central nervous system. We therefore disrupted the Mcph1 gene in mice. Mutant mice exhibit microcephaly, due to defects in the embryonic development of the cerebral cortex. Deletion of Mcph1 does not affect the proliferation rate of neuronal progenitor cells, but compromises their self-renewal capacity. In contrast, Mcph1 mutant embryos show a higher cell cycle exit of neuronal progenitor cells, suggesting a disturbed cell division mode. Indeed, we found that deletion of Mcph1 promotes neuronal progenitor cells to undergo neurogenic asymmetric cell division. Mcph1-deficient neuronal progenitor cells show a misregulation of the centrosomal localization of Chk1 in G2-phase of the cell cycle. Centrosomal Chk1 inhibits mitotic entry through temporary inhibition of Cdc25B and Cdk1. As a result, cells prematurely activate Cdk1 leading to early mitotic entry thereby uncoupling the cell cycle from the centrosome cycle. The uncoupling of these two cycles results in mitotic spindle defects and apoptotic cells, due to mitotic failure. Moreover, defects of the mitotic spindle alignment affects the orientation of the cleavage plane of dividing neuronal progenitor cells, thereby promoting neurogenic asymmetric divisions. We conclude that MCPH1 regulates the type of neuronal progenitor division mode by ensuring proper mitotic entry through the centrosomal Chk1-Cdc25B-pathway. Hence, MCPH1 is important for the amplification of the neuronal progenitor pool and consequently a sufficient neuron production during embryonic neurogenesis to determine the brain size.