Dynamic Control of Translation During Adult Neurogenesis

Neurons are highly compartmentalized into specific functional units including dendrites, axons and somas. While most messenger RNAs (mRNAs) are constantly used to produce proteins, a subset will remain translationally silent and targeted to aforementioned subcellular structures in order to be available “on demand” upon intra- and extracellular signals. This uncoupling of general availability of mRNAs from actual translation into proteins facilitates immediate response to environmental changes without involving signaling to the soma, which may be far away from axon endings. Furthermore, this way cells avoid excess production of proteins, which is the most energy consuming process within the cell. Adult neural stem cells (NSCs) reside in a thin layer lining the lateral ventricles of the brain and constantly produce progeny that migrates to the olfactory bulb and differentiates into several subtypes of interneurons. Their gene expression has been intensively studied using RNA-based technologies, assuming that mRNA availability readily translates into protein abundance. Whether there is indeed a linear relationship and to which level it is maintained during state transitions throughout neurogenesis has been elusive. Here we studied both global- and transcript-specific translation over multiple stages of neurogenic differentiation. We uncovered dynamic changes of global protein synthesis peaking at stages of proliferation and neuronal integration. Further, using RiboTag mouse models, we showed that transcript abundance and its ribosome-binding shows highest linearity in NSCs that becomes increasingly divergent with the progression of differentiation. NSCs’ transition to early neuroblasts involves translational repression of a subset of mRNAs including both multiple members of the protein synthesis machinery as well as the key pluripotency factor Sox2. In silico motif analysis within this cluster of transcripts led to identification of a pyrimidine-rich motif (PRM) that predicts sensitivity of their translation to the activity of mammalian target of rapamycin complex 1 (mTORC1). Indeed, pharmacological inhibition of mTORC1 reduced ribosome binding of PRM- containing transcripts, while PRM-free transcripts were not affected. Together, this data provides a comprehensive view on the dynamic control of translation during neurogenic differentiation in vivo and uncovers a post-transcriptional mechanism that allows fast and robust repression of pluripotency factors in NSCs as they differentiate