A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration

Zeb2 is a homeodomain transcription factor that plays pleiotropic functions during embryogenesis, but its role for midbrain dopaminergic (mDA) neuron development is unknown. Here we report that Zeb2 is highly expressed in progenitor cells in the ventricular zone of the midbrain floor plate and downregulated in postmitotic neuroblasts. Functional experiments show that Zeb2 expression in the embryonic ventral midbrain is dynamically regulated by a negative feedback loop that involves miR-200c. We also find that Zeb2 overexpression reduces the levels of CXCR4, NR4A2, and PITX3 in the developing ventral midbrain in vivo, resulting in migration and mDA differentiation defects. This phenotype was recapitulated by miR-200c knockdown, suggesting that the Zeb2-miR-200c loop prevents the premature differentiation of mDA progenitors into postmitotic cells and their migration. Together, our study establishes Zeb2 and miR-200c as critical regulators that maintain the balance between mDA progenitor proliferation and neurogenesis.