+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Journal of Neuroscience 32(38): 13292-13308



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 051281607

Download citation: RISBibTeXText

PMID: 22993445

DOI: 10.1523/jneurosci.2124-12.2012


Related references

APC/C (Cdh1) controls the proteasome-mediated degradation of E2F3 during cell cycle exit. Cell Cycle 11(10): 1999-2005, 2012

Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Developmental Biology 258(2): 319-333, 2003

An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128(5): 947-959, 2007

Homeodomain transcription factor Phox2a, via cyclic AMP-mediated activation, induces p27Kip1 transcription, coordinating neural progenitor cell cycle exit and differentiation. Molecular and Cellular Biology 26(23): 8826-8839, 2006

Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit. Proceedings of the National Academy of Sciences of the United States of America 114(40): 10660-10665, 2017

Sumoylation controls retinal progenitor proliferation by repressing cell cycle exit in Xenopus laevis. Developmental Biology 347(1): 180-194, 2010

The light cycle controls the hatching rhythm in Bombyx mori via negative feedback loop of the circadian oscillator. Archives of Insect Biochemistry and Physiology 96(2):, 2017

E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop. Molecular and Cellular Biology 27(1): 65-78, 2007

MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proceedings of the National Academy of Sciences of the United States of America 102(35): 12449-12454, 2005

Coordinating progenitor cell cycle exit and differentiation in the developing vertebrate retina. Neurogenesis 3(1): E1161697, 2016

Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1. Neuron Glia Biology 3(3): 221-231, 2007

Pax6 is required for normal cell-cycle exit and the differentiation kinetics of retinal progenitor cells. Plos one 8(9): E76489, 2013

A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Developmental Cell 12(4): 631-643, 2007

A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. Faseb Journal 20(10): 1730-1732, 2006

Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2. Developmental Cell 35(4): 483-496, 2015