ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development

Zinc-finger E-box binding homeobox 1 (Zeb1) is a key regulator of epithelial-mesenchymal transition and cancer metastasis. Mutation of ZEB1 is associated with human diseases and defective brain development. Here we show that downregulation of Zeb1 expression in embryonic cortical neural progenitor cells (NPCs) is necessary for proper neuronal differentiation and migration. Overexpression of Zeb1 during neuronal differentiation, when its expression normally declines, blocks NPC lineage progression and disrupts multipolar-to-bipolar transition of differentiating neurons, leading to severe migration defects and subcortical heterotopia bands at postnatal stages. ZEB1 regulates a cohort of genes involved in cell differentiation and migration, including Neurod1 and Pard6b. The interaction between ZEB1 and CTBP2 in the embryonic cerebral cortex is required for ZEB1 to elicit its effect on the multipolar-to-bipolar transition, but not its suppression of Neurod1. These findings provide insights into understanding the complexity of transcriptional regulation during neuronal differentiation. [Display omitted] •ZEB1 is expressed in embryonic neural progenitor cells, but not in neurons•ZEB1 blocks lineage progression to neuronal commitment and cell migration•Prolonged Zeb1 expression leads to subcortical band heterotopia•ZEB1 acts synergistically with CTBP2 to regulate cell morphology Neural progenitor cells in the developing brain undergo a precisely controlled transition from proliferation to differentiation. Wang et al. report that ZEB1 expression is restricted to neural progenitor cells to ensure the transition to neuronal generation. Forced expression of ZEB1 blocks neuronal migration through interaction with CTBP2, leading to cortical abnormalities.