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

Item Type:Article
Title:A unilateral negative feedback loop between miR-200 microRNAs and Sox2/E2F3 controls neural progenitor cell-cycle exit and differentiation
Creators Name:Peng, C. and Li, N. and Ng, Y.K. and Zhang, J. and Meier, F. and Theis, F.J. and Merkenschlager, M. and Chen, W. and Wurst, W. and Prakash, N.
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.
Keywords:Biological Models, Cell Count, Cell Cycle, Cell Death, Cell Differentiation, Cultured Cells, Cercopithecus aethiops, DEAD-box RNA Helicases, Deoxyuridine, Developmental Gene Expression Regulation, E2F3 Transcription Factor, Green Fluorescent Proteins, Homeodomain Proteins, Inbred C57BL Mice, Mammalian Embryo, Mesencephalon, MicroRNAs, Mutation, Nerve Tissue Proteins, Neural Stem Cells, Rhombencephalon, Ribonuclease III, Serotonin, Signal Transduction, SOXB1 Transcription Factors, Transcription Factor Brn-3A, Transgenic Mice, Transcription Factors, Transfection, Animals, Mice
Source:Journal of Neuroscience
ISSN:0270-6474
Publisher:Society for Neuroscience (U.S.A.)
Volume:32
Number:38
Page Range:13292-13308
Date:19 September 2012
Official Publication:https://doi.org/10.1523/JNEUROSCI.2124-12.2012
PubMed:View item in PubMed

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