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

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. In this article, Cremisi, Studer, and colleagues found that miR-21 is induced by FGF8 and represses the translation of COUP-TFI, a key regulator of cortical identity, by binding to its 3′UTR in vitro and in vivo. This indicates that an in vitro model of ESC corticalization can be adopted to gain insight into developmental mechanisms required for area mapping.