During neocortical development, there are two important events, including expansion of the neural progenitor pool through symmetric divisions, and generation of neurons via asymmetrical divisions that lead to a serial process of neuronal polarization, migration, and layer-type specific phenotype acquisition. The mechanisms underlying these processes remain poorly elucidated. Here, we show that the transcription factor Zeb1 regulates the orientation of the cleavage plane of dividing neural progenitors, neuronal polarity, and migration. Upon Zeb1 removal, the cleavage plane of mitotic neural progenitors fails to orientate vertically, resulting in random orientation and premature neuronal differentiation. Consequently, these extra number of precociously produced neurons migrate aberrantly to the upper layer. Mechanistically, we show that Zeb1 suppresses Pak3, a p21-activated serine/threonine protein kinase, through formation of a functional repressing complex together with methyltransferase PRMT5 and Pak3. Our results reveal that Zeb1 plays an essential role in neocortical development and may provide insights into the mechanisms responsible for cortical developmental diseases.
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This study was supported by funds from Ministry of Science and Technology of the People’s Republic of China (2017YFA0102900 to WQG), National Natural Science Foundation of China (81872406, 81630073 to WQG and 81773115 to WX), Science and Technology Commission of Shanghai Municipality (16JC1405700 to WQG), High Peak IV fund from Education Commission of Shanghai Municipality on Stem Cell Research (to WQG) and KC Wong foundation (to WQG) and SJTU interdisciplinary grant (YG2017MS52 to WX).
Conflict of interest
The authors declare that they have no conflict of interest.
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Edited by N. Bazan