Let‐7 and miR‐125 cooperate to prime progenitors for astrogliogenesis

The molecular basis of astrocyte differentiation and maturation is poorly understood. As micro RNA s have important roles in cell fate transitions, we set out to study their function during the glial progenitor cell ( GPC ) to astrocyte transition. Inducible deletion of all canonical micro RNA s in GPC s in vitro led to a block in the differentiation to astrocytes. In an unbiased screen, the reintroduction of let‐7 and miR‐125 families of micro RNA s rescued differentiation. Let‐7 and miR‐125 shared many targets and functioned in parallel to JAK ‐ STAT signaling, a known regulator of astrogliogenesis. While individual knockdown of shared targets did not rescue the differentiation phenotype in micro RNA ‐deficient GPC s, overexpression of these targets in wild‐type GPC s blocked differentiation. This finding supports the idea that micro RNA s simultaneously suppress multiple mRNA s that inhibit differentiation. MicroRNA‐regulated transcripts exhibited concordant changes during in vivo differentiation and were enriched for a gene set upregulated in glioblastomas, consistent with validity of using the in vitro model to study in vivo events. These findings provide insight into the micro RNA s and the genes they regulate in this important cell fate transition.