The Role Of Transcription Factor Zeb1 In The Developmental Cerebral Cortex

Background: The cerebral cortex is an important part of brain,which plays a critical role in somatic motor modulation as well as emotional and conscious formation.The abnormal cerebral cortex development gives rise to lots of developmental diseases,such as microcephaly,lissencephaly etc.Neural stem cells are origin of all cells in the brain and their proper proliferation and differentiation are critical for cerebral cortex development.During the cerebral cortex development,transcription factors participate in this process deeply,which modulate series of radial glial cell's cellular behaviors.In our studies,we focus on Zeb1,which is closely related with bHLH transcription factor family that play a key role in the process of nervous system development and post-injury repair.Object: The the molecular mechanism of cerebral cortex development remains poorly elucidated.We performed this research to decipher the role and mechanisms of Zeb1 in cerebral cortex development.Methods:(1)The expression pattern and cellular location of Zeb1 in developmental cortex were detected by Western-blotting and immunofluorescence.(2)Zeb1 knockout mice were used to detect the effects of Zeb1 deficiency on cortical lamination and division modes of radial glial cells.(3)In utero electroporation(IUE)was performed to detect the postmitotic neuronal migration when Zeb1 was knockdown.(4)Microarray and qPCR studies were performed to screen the Zeb1 downstream target genes that were further confirmed by luciferase and ChIP.(5)Immunoprecipitation and mass spectrum studies were performed to search the coeffector of Zeb1 on modulating downstream target genes and detect which one of them dominated the modulated process.Results:(1)Zeb1 was highly expressed in developmental cerebral cortex and specifically localized in the radial glial cells.(2)Null of Zeb1 caused cerebral cortex malformation and abnormal postmitotic neuron position.(3)Null of Zeb1 inhibited radial glial cell proliferation and promoted differentiation,thereby tending to withdraw from cell cycles.(4)Null of Zeb1 promoted radial glial cell asymmetric division and the random orientation of division plane distribution.(5)Interference of Zeb1 promoted premature neuron migration rapidly.(6)Zeb1 repressed downstream target gene Pak3 through recruiting PRMT5 and overexpression of Pak3 was able to rescue the phenotype of aberrant premature neuronal migration induced by interference of Zeb1.Conclusion: Zeb1 plays a key role in the process of cerebral cortex development and null of Zeb1 caused abnormal cerebral cortex development.Zeb1 enabled the modulatation of the proliferation and differentiation of radial glial cells as well as postmitotic migration.Zeb1 repressed Pak3 transcription through recruiting PRMT5,by which modulating postmitotic neuronal migration.Collectively,our results reveal that Zeb1 plays an essential role in neocortical development and may provide insights into the mechanisms responsible for cortical developmental diseases.