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Abstract

In mammals, the process of neurogenesis consists in the generation of various types of neuronal and glial cells from neural stem cells (NSCs). It begins intensively at the embryonic stage and continues through the whole adulthood. In adult rodents, neurogenesis is mainly located in two regions: the ventricular-subventricular zone (V-SVZ) of the lateral ventricles and the dentate gyrus of the hippo-campus. In the last two decades huge progress has been made to characterize the process in detail and to get further insights of its regulation. However, still some fundamental questions remain unanswered. Among those, whether post-transcriptional regulation plays a critical role in NSC activation and differentiation. In this project, I investigated protein synthesis and its modulation upon activation of NSCs using the mouse adult brain as an experimental model. The analysis of the nascent synthesized peptides in NSCs and early neuroblasts (ENBs) of the same lineage revealed that the level of global protein synthesis decreases upon the transition from NSCs to ENBs. The transcriptome and translatome analysis of NSCs and ENBs clearly showed an active involvement of post-transcriptional regulation in gene expression at the onset of NSC differentiation. In particular, translation of neuronal specification transcripts such as Sp8 and Dusp4 was enhanced. On the contrary, the translation of some mRNAs carrying the Terminal Oligo Pyrimidine (TOP) and the Pyrimidine Rich Motif (PRM) such as Sox2 and Rpl18 were selectively repressed. At this transition, we also observed a drop of mTOR activity upon cell cycle exit that was causally linked to repression of TOP- and PRM-transcripts. Altogether, our study underscored the role of protein synthesis and its regulation in NSC differentiation. It also demonstrated a causal link between cell cycle exit, TOR activity and exit of the stem cell state.