A eutherian-specific microRNA controls the translation of Satb2 in a model of cortical differentiation

Cerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different cortical layers. These transcription factors are crucial for the identity of the different neurons, but the mechanisms controlling their expression in distinct cells are only partially known. Here we investigate the expression and stability of the mRNAs of Tbr1, Bcl11b, Fezf2, Satb2 and Cux1 in single developing mouse cortical cells. We focus on Satb2 and find that its mRNA expression occurs much earlier than its protein synthesis and in a set of cells broader than expected, suggesting an initially tight control of its translation, which is subsequently de-repressed at late developmental stages. Mechanistically, Satb2 3’UTR modulates protein translation of GFP reporters during mouse corticogenesis. By in vitro pull-down of Satb2 3’UTR-associated miRNAs, we select putative miRNAs responsible for SATB2 inhibition, focusing on those strongly expressed in early progenitor cells and reduced in late cells. miR-541, an Eutherian-specific miRNA, and miR-92a/b are the best candidates and their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate that RNA interference plays a major role in the timing of cortical cell identity and may be part of the toolkit involved in specifying supra-granular projection neurons.