A unilateral negative feedback loop between miR-200 microRNAs and Sox2/E2F3 controls neural progenitor cell-cycle exit and differentiation

Changgeng Peng, Na Li, Yen Kar Ng, Jingzhong Zhang, Florian Meier, Fabian J. Theis, Matthias Merkenschlager, Wei Chen, Wolfgang Wurst, Nilima Prakash

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

82 Zitate (Scopus)

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; Dicer1flox/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.

OriginalspracheEnglisch
Seiten (von - bis)13292-13308
Seitenumfang17
FachzeitschriftJournal of Neuroscience
Jahrgang32
Ausgabenummer38
DOIs
PublikationsstatusVeröffentlicht - 19 Sept. 2012

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