The repressor element silencing transcription factor (REST) plays a crucial role in the differentiation of neural progenitor cells (NPCs). Effector proteins of REST are C-terminal domain small phosphatases (CTDSPs), which reduce polymerase II activity on genes required for neurogenesis. miR-26b regulates neurogenesis in zebrafish by targeting ctdsp2 mRNA, but the molecular events triggered by this microRNA remain unknown. Here we show in a murine embryonic stem cell differentiation paradigm that inactivation of miR-26 family members disrupts the formation of neurons and astroglia and arrests neurogenesis at the neural progenitor level. We further show that miR-26 directly targets Rest, thereby inducing the expression of a large set of REST complex-repressed neuronal genes including miRs required for the induction of the neuronal gene expression program. Our data identify the miR-26 family as the trigger of a self-amplifying system required for neural differentiation that acts upstream of REST-controlled miRs.

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Neurogenesis is a finely tuned process, which depends on the balanced execution of expression programs that regulate cellular differentiation and proliferation. Different molecular players ranging from transcription factors to chromatin modulators control these programs. Adding to the complexity, also non-coding (nc)RNAs take part in this process. Here we analyzed the function of the long non-coding (lnc)RNA Malat1 during neural embryonic stem cell (ESC) differentiation. We find that deletion of Malat1 leads to inhibition of proliferation of neural progenitor cells (NPCs). Interestingly, this co-insides with an increase in the expression of miR-26 family members miR-26a and miR-26b in differentiating ESCs. Inactivation of miR-26a/b rescues the proliferative phenotype of Malat1 knockout (KO) cells and leads to accelerated neuronal differentiation of compound Malat1KO/mir-26KO ESCs. Together our work identifies a so far unknown interaction between Malat1 and miR-26 in the regulation of NPC proliferation and neuronal differentiation.