Function Of The Middle Domain Of MCPH1 In The Development Of Cerebral Cortex And Gonads

Human autosomeal recessive primary microcephaly(MCPH)is a neurodevelopment disorder characterized by a marked reduction of brain size.So far,29 gene loci have been identified to be responsible for MCPH.The MCPH1 gene is the first gene identified to be responsible for MCPH type 1.Previous studies of our group had shown that Mcph1-deletion mice show a decreased level of Chkl in the centrosome,this event will lead to aberrant Cdk1 activation and premature mitotic entry of neuroprogenitor.Disturbed centrosome maturation and activities results in an exchange the division mode of neuroprogenitor,which ultimately affects the development of the cerebral cortex because of exhaustion of the neuroprogenitor pool.Strikingly,MCPH1 is also involved in gonad development.Mouse of Mcph1 knockout and lacking the N-terminal BRCT domain are infertility with testicular and ovarian atrophy.In addition,it has been shown that MCPH1 mediates dimerization of βTrCP2 to promote the degration of Cdc25a via its middle domain,which balances the proliferation and differentiation of neuroprogenitor cells.However,the function of the middle domain in cerebral cortex and gonad development remains elusive.The middle domain of MCPH1 is mainly encoded by exon 8.To investigate the function of the middle domain,we generated a conditional knockout mouse model lacking exon 8 of Mcph1.Crossing of Mcph1-e8flox/flox mice with the EIIa-Cre mice,extensively expressing the Cre recombinase in early embryo,leading to the deletion of exon 8.The homozygouse mutation was named Mcph1-Δe8.In this study,we found that Mcph1-Δe8 mice are viable,but exhibit reduced brain size with a thinner cortex due to premature differentiation of neuronal progenitor cells.In addition,Mcph1-Δe8 mice showed a block in reproductive organ development,characterized by testis atrophy and lacking ovaries,respectively.Mcph1-Δe8 MEF cells show the premature chromosome condensation phenotype.In summary,the middle domain of MCPH1 play an important role in brain size and gonad development as well as cellular activities.This study provides a comprehensive understanding of the function of MCPH 1 in microcephaly and gonad development.