Onset of differentiation is posttranscriptionally controlled in adult neural stem cells

Abstract

The contribution of posttranscriptional regulation of gene expression to neural stem cell differentiation during tissue homeostasis remains elusive. Here we show highly dynamic changes in protein synthesis along differentiation of stem cells to neurons in vivo. Examination of individual transcripts using RiboTag mouse models reveals that neural stem cells efficiently translate abundant transcripts, whereas translation becomes increasingly controlled with the onset of differentiation. Stem cell generation of early neuroblasts involves translational repression of a subset of mRNAs including the stem cell-identity factors Sox2 and Pax6 as well as translation machinery components. In silico motif analysis identifies a pyrimidine-rich motif (PRM) in this repressed subset. A drop in mTORC1 activity at the onset of differentiation selectively blocks translation of PRM-containing transcripts. Our data uncovers how a drop in mTORC1 allows robust simultaneous posttranscriptional repression of key stem cell identity-factors and translation-components and thereby stemness exit and migration.