Zeb1 is important for proper cleavage plane orientation of dividing progenitors and neuronal migration in the mouse neocortex

Cell Death Differ. 2019 Nov;26(11):2479-2492. doi: 10.1038/s41418-019-0314-9. Epub 2019 Mar 11.


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.

MeSH terms

  • Animals
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Ependymoglial Cells / cytology*
  • Mice
  • Mice, Knockout
  • Neocortex / embryology*
  • Neural Stem Cells / cytology*
  • Neurogenesis / physiology*
  • Neurons / cytology*
  • Promoter Regions, Genetic / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*
  • p21-Activated Kinases / metabolism


  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Pak3 protein, mouse
  • p21-Activated Kinases