Abstract Cortical expansion in the primate brain relies on the presence and the spatial enlargement of multiple germinal zones during development and on a prolonged developmental period. In contrast to other mammals, which have two cortical germinal zones, the ventricular zone (VZ) and subventricular zone (SVZ), gyrencephalic species display an additional germinal zone, the outer subventricular zone (OSVZ), which role is to increase the number and types of neurons generated during corticogenesis. How the OSVZ emerged during evolution is poorly understood but recent studies suggest a role for non-coding RNAs, which allow tight regulations of transcriptional programs in time and space during development (Dehay et al. 2015; Arcila et al., 2014). Here, using in vivo functional genetics, single-cell RNA sequencing, live imaging and electrophysiology to assess progenitor and neuronal properties in mice, we identify two ferret and human OSVZ-enriched microRNAs (miR), miR-137 and miR-122, which regulate key cellular features associated with cortical expansion. MiR-137 promotes basal progenitor self-replication and superficial layer neuron fate, while miR-122 slows down neuronal differentiation pace. Together, these findings support a cell-type specific role for miR-mediated transcriptional regulation in cortical expansion.

MiR-137 and miR-122, two outer subventricular zone-enriched non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation