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Stem Cell Reports. 2018 Sep 11;11(3):756-769. doi: 10.1016/j.stemcr.2018.08.002. Epub 2018 Aug 30.

The microRNA miR-21 Is a Mediator of FGF8 Action on Cortical COUP-TFI Translation.

Author information

1
Scuola Normale Superiore, Piazza dei Cavalieri, 7, Pisa 56126, Italy.
2
Université Côte d'Azur (UCA), CNRS, Inserm, iBV, 06108 Nice, France.
3
Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany.
4
Scuola Normale Superiore, Piazza dei Cavalieri, 7, Pisa 56126, Italy; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745 Jena, Germany.
5
Scuola Normale Superiore, Piazza dei Cavalieri, 7, Pisa 56126, Italy; Istituto di Biofisica CNR, Via Moruzzi 1, 56124 Pisa, Italy. Electronic address: federico.cremisi@sns.it.

Abstract

The morphogen FGF8 plays a pivotal role in neocortical area patterning through its inhibitory effect on COUP-TFI/Nr2f1 anterior expression, but its mechanism of action is poorly understood. We established an in vitro model of mouse embryonic stem cell corticogenesis in which COUP-TFI protein expression is inhibited by the activation of FGF8 in a time window corresponding to cortical area patterning. Interestingly, overexpression of the COUP-TFI 3'UTR reduces the inhibitory effect of FGF8 on COUP-TFI translation. FGF8 induces the expression of few miRNAs targeting COUP-TFI 3'UTR in silico. We found that the functional inhibition of miR-21 can effectively counteract the inhibitory effect of FGF8 in vitro and regulate COUP-TFI protein levels in vivo. Accordingly, miR-21 expression is complementary to COUP-TFI expression during corticogenesis. These data support a translational control of COUP-TFI gradient expression by FGF8 via miR-21 and contribute to our understanding of how regionalized expression is established during neocortical area mapping.

KEYWORDS:

COUP-TFI; ESC; FGF8; Nr2f1; cortex; corticogenesis; in utero electroporation; mir-21; patterning

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