DEVELOPMENTAL ESTABLISHMENT OF ADULT NEURAL STEM CELLS IN THE MAMMALIAN BRAIN

Quiescence is essential for the long-term maintenance of adult stem cells and tissue homeostasis and the adult hippocampal dentate gyrus (DG) neural stem cells (NSCs) are a mostly quiescent population whose activation is tightly controlled by a complex range of signals integrating extrinsic and intrinsic signals. Our study showed that the same population of Hopx+ NSCs contribute to developmental and adult DG neurogenesis. In development, these NSCs are highly proliferative, gradually attenuating or losing their proliferative capacity as development progresses, with some proportion of cells depleting. For hippocampal neurogenesis, this proliferative status delineates the transition point between development and adult NSCs. Identifying the origins and emergence of the initial quiescent pool and characterizing its acquisition is imperative to understanding the behavior of adult NSCs. Here through transcriptomic profiling, we identify that Hopx+ neural progenitors that populate the dentate gyrus of the primordial hippocampus giving rise to the putative adult RGL responsible for adult neurogenesis in mice and highlight that gross molecular events take place during the first postnatal weeks in which a quiescent pool is being established. Single-cell analysis of early neural precursors identifies the early establishment of stem cell heterogeneity and a single major trajectory toward quiescent. Through the reconstruction of a continuous developmental trajectory across early postnatal development, our study reveals the molecular signatures, events, and regulatory networks involved in establishing a naïve quiescent pool and acquisition of an adult signature, providing a comprehensive resource of single-cell transcriptomes. We find that metabolic, cell cycle shifts and chromatin modifications, exemplify the neural precursor’s molecular continuum, followed by changes in cellular morphogenesis, increases in ROS production, and active niche signaling integration, low protein translation capacity, and the emergence of a glial signature that occurs both gradually in a step-wise and state-dependent manner that tracks with age. Importantly we find that cell cycle arrest is not the hallmark of the adult quiescent RGL signature but a demarcation of its progression. Together these data identify predictive pseudo-timing of gene combinations expressed or downregulated and molecular events that can be further investigated to either enhance or prevent NSC quiescence or maturation