The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice

MCPH1 is the first gene identified to be responsible for the human autosomal recessive disorder primary microcephaly (MCPH). Mutations in the N-terminal and central domains of MCPH1 are strongly associated with microcephaly in human patients. A recent study showed that the central domain of MCPH1, which is mainly encoded by exon 8, interacts with E3 ligase beta TrCP2 and regulates the G2/M transition of the cell cycle. In order to investigate the biological functions of MCPH1's central domain, we constructed a mouse model that lacked the central domain of MCPH1 by deleting its exon 8 (designated as Mcph1-Delta e8). Mcph1-Delta e8 mice exhibited a reduced brain size and thinner cortex, likely caused by a compromised self-renewal capacity and premature differentiation of Mcph1-Delta e8 neuroprogenitors during corticogenesis. Furthermore, Mcph1-Delta e8 mice were sterile because of a loss of germ cells in the testis and ovary. The embryonic fibroblasts of Mcph1-Delta e8 mice exhibited premature chromosome condensation (PCC). All of these findings indicate that Mcph1-Delta e8 mice are reminiscent of MCPH1 complete knockout mice and Mcph1-Delta BR1 mice. Our study demonstrates that the central domain of MCPH1 represses microcephaly, and is essential for gonad development in mammals.