Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.

20Adult neural stem cells are largely quiescent, and require transcriptional reprogramming 21 to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms 22 that underlie the rapid transcriptional overhaul during NSC activation remain undefined. 23Here, we identify the genome-wide chromatin accessibility differences between primary 24 neural stem and progenitor cells in quiescent and activated states. We show that these 25 distinct cellular states exhibit both shared and unique chromatin profiles, which are both 26 associated with gene regulation. Interestingly, we find that accessible chromatin states 27 specific to quiescent or activated cells are active enhancers bound by pro-neurogenic 28 and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters 29 harboring constitutively accessible chromatin enriched for particular core promoter 30 elements that are functionally associated with translation and metabolic functions. 31Together, our findings reveal how accessible chromatin states regulate a transcriptional 32 overhaul and drive the switch between quiescence and proliferation in NSC activation. 33 34 46In vivo, the majority of NSCs reside in a state of quiescence 10 . Quiescent NSCs (qNSCs) 47 have exited the cell cycle but can be prompted by intrinsic or extrinsic cues to "activate" 48 and re-enter the cell cycle (we refer to these cells as activated NSCs, or aNSCs). Once 49 activated, aNSCs proliferate and may return to quiescence and self-renew, or 50 differentiate into neurons or glia. Activation of qNSCs is the first critical step in 51 neurogenesis in the adult brain, and is enhanced in response to damage (e.g. stroke) or 52 environmental stimuli such as parabiosis [11][12][13] . Evidence shows that decreased 53 neurogenesis with age occurs due to reduced activation of qNSCs, senescence of the 54 NSC niche, and exhaustion of the qNSC pool [14][15][16][17] . Accumulation of qNSCs has also been 55 observed in a rodent model for neurodevelopmental disorders, suggesting that a careful 56 balance of NSC quiescence and activation is necessary for healthy cognitive function 18 . 57However, the precise mechanisms that regulate this balance and prompt qNSCs to re-58 enter the cell cycle in the healthy mammalian brain are mostly unknown. 59 60 Recent studies reported that quiescent and activated NSCs employ cell type-specific 61 mechanisms to support their functionality, including distinct metabolic states and 62 differences in proteostasis [19][20][21] . Transcriptional profiling of qNSCs and aNSCs revealed 63 both shared and distinct transcriptional signatures in the two cell types, indicating that a 64 transcriptional overhaul occurs at a subset of genes during the process of NSC 65 activation 10,19,22,23 . For example, genes involved in cell proliferation, lipid metabolism, and 66 protein homeostasis were differentially expressed in quiescent and activated NSCs. 67 Similar changes have also been observed using in vitro models of NSC quiescence and 68 activation...

of endothelial cells in organoid maintenance, and the mechanism of cyclical glucose fluctuations in inducing beta cell functionality, both of which could potentially be leveraged to enhance the clinical potential of pluripotent stem cell-derived beta-like cells. Wherever these findings lead us, this work is certainly a timely homage to the spirit of scientific innovation exemplified by Banting and colleagues nearly a century ago. DECLARATION OF INTERESTSM.C.N. has a patent licensed to Sernova Inc. and is a scientific consultant for Sigilon Therapeutics.