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

Shanzheng Yang,Ernest Arenas,Enrique M Toledo,Per Uhlén,Changgeng Peng,Pedro Rosmaninho,Diogo S Castro

doi:10.1038/s42003-018-0080-0

Shanzheng Yang, Ernest Arenas + Show 5 more

Open Access

https://doi.org/10.1038/s42003-018-0080-0

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Abstract

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.

Highlights

Zeb[2] is a homeodomain transcription factor that plays pleiotropic functions during embryogenesis, but its role for midbrain dopaminergic neuron development is unknown
The first postmitotic cell generated in the dopaminergic lineage is the medial neuroblast[19], a cell type characterized by the expression of the nuclear receptor Nr4a2, which is required for the generation of midbrain dopaminergic (mDA) neurons[20]
We found that Zeb[2] is expressed in ventricular zone (VZ) progenitors and downregulated in postmitotic neuroblasts by a negative feedback loop established with miR200c

Summary

Introduction

Zeb[2] is a homeodomain transcription factor that plays pleiotropic functions during embryogenesis, but its role for midbrain dopaminergic (mDA) neuron development is unknown. We find that Zeb[2] 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. Zeb[2] gain-of-function or miR-200c knockdown reduced the levels of NR4A2 in the developing ventral midbrain, preventing the premature differentiation of mDA progenitors into postmitotic cells as well as their migration and maturation. Our results identify Zeb[2] and miR-200c as important regulators of the balance between mDA progenitor maintenance and neurogenesis

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