A Unilateral Negative Feedback Loop Between MiR-200 MicroRNAs and Sox2/E2F3 Controls Neural Progenitor Cell-cycle Exit and Differentiation

Overview

Journal J Neurosci

Specialty Neurology

Date 2012 Sep 21

PMID 22993445

Citations 51

Authors

Changgeng Peng

Na Li

Yen-Kar Ng

Jingzhong Zhang

Florian Meier

Fabian J Theis

Matthias Merkenschlager

Wei Chen

Wolfgang Wurst

Nilima Prakash

Affiliations

Soon will be listed here.

Abstract

MicroRNAs have emerged as key posttranscriptional regulators of gene expression during vertebrate development. We show that the miR-200 family plays a crucial role for the proper generation and survival of ventral neuronal populations in the murine midbrain/hindbrain region, including midbrain dopaminergic neurons, by directly targeting the pluripotency factor Sox2 and the cell-cycle regulator E2F3 in neural stem/progenitor cells. The lack of a negative regulation of Sox2 and E2F3 by miR-200 in conditional Dicer1 mutants (En1(+/Cre); Dicer1(flox/flox) mice) and after miR-200 knockdown in vitro leads to a strongly reduced cell-cycle exit and neuronal differentiation of ventral midbrain/hindbrain (vMH) neural progenitors, whereas the opposite effect is seen after miR-200 overexpression in primary vMH cells. Expression of miR-200 is in turn directly regulated by Sox2 and E2F3, thereby establishing a unilateral negative feedback loop required for the cell-cycle exit and neuronal differentiation of neural stem/progenitor cells. Our findings suggest that the posttranscriptional regulation of Sox2 and E2F3 by miR-200 family members might be a general mechanism to control the transition from a pluripotent/multipotent stem/progenitor cell to a postmitotic and more differentiated cell.

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