The miR-26 family regulates neural differentiation-associated microRNAs and mRNAs by directly targeting REST

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.