MIR3607 regulates cerebral cortex development via activation of Wnt/βCat signaling

The evolutionary expansion of the mammalian cerebral cortex is recapitulated during embryonic development in large mammals, but the underlying genetic mechanisms remain mostly unknown. Previous transcriptomic analyses of the developing ferret cortex identify candidate genes related to the expansion of germinal layers and cortex size. Here we focused on MIR3607, a microRNA differentially expressed between germinal layers of the large human and ferret cortex, not expressed in the small mouse cortex. Expression of MIR3607 in mouse embryos at E14.5 leads to increased progenitor cell proliferation. This is reflected in transcriptomic changes, which also reveal increased Wnt/βCatenin signaling. Expression of MIR3607 at E12.5, when progenitor cells expand, causes amplification and severe delamination of apical progenitors, leading to rosette formation. This is rescued by co-expressing Adenomatous Polyposis Coli, inhibitor of canonical Wnt signaling. A similar phenotype is produced in human cerebral organoids. Our findings demonstrate that MIR3607 expands and delaminates apical progenitor cells via activating Wnt/βCatenin, and suggest that a secondary loss of expression in mouse may underlie their reduction in cortex size during recent evolution.