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

Abstract

The molecular basis of astrocyte differentiation and maturation is poorly understood. As microRNAs 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 microRNAs in GPCs 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 microRNAs 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 microRNA-deficient GPCs, overexpression of these targets in wild-type GPCs blocked differentiation. This finding supports the idea that microRNAs simultaneously suppress multiple mRNAs 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 microRNAs and the genes they regulate in this important cell fate transition.

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

“…LIN28A/B and let-7 thereby form a bistable switch that operates to maintain stemness or induce differentiation (for review, see Thornton and Gregory 2012). In the brain, NSC maintenance and differentiation (Nishino et al 2008;Yu et al 2015) as well as glial progenitor cell differentiation to astrocytes (Shenoy et al 2015) are regulated by let-7 family members and their targets.…”

MicroRNAs in neural development: from master regulators to fine-tuners

“…Once miR-153 levels are decreased, NFIA/B accumulates and NPCs acquire gliogenic competence (Tsuyama et al, 2015). Additional miRNAs that are important in glial cell lineage decisions include let-7 family members (Gökbuget et al, 2015;Patterson et al, 2014;Shenoy et al, 2015).…”

Astro‐logics with micro RNA s

“…Together with the JAK‐STAT signaling pathway, which is crucial for astrocyte differentiation in vivo (Bonni et al , ; He et al , ), the miRNAs convey robustness to acquisition of the astrocyte fate program (Fig A). Shenoy et al () demonstrate that Let‐7 and miR‐125 interlace with JAK‐STAT into a higher‐order network, required for regulation of astrocyte differentiation. However, the cooperation between these specific miRNAs and JAK‐STAT signaling is not trivial and depends on cellular context.…”

“…(A) Diagram describing the mechanism identified by Shenoy et al (), for in vitro differentiation of glial progenitor cells into astrocytes; JAK‐STAT signaling initiates transcription of astrocyte‐specific mRNAs and functions in concert with miR‐125 and Let‐7. The miRNAs serve to silence the expression of mRNAs that are disallowed, in the sense that they block astrocyte differentiation.…”