Abstract
The quiescence, activation, and subsequent neurogenesis of neural stem cells (NSCs) play essential roles in the physiological homeostasis and pathological repair of the central nervous system. Previous studies indicate that transmembrane protein Ttyh1 is required for the stemness of NSCs, whereas the exact functions in vivo and precise mechanisms are still waiting to be elucidated. By constructing Ttyh1-promoter driven reporter mice, we determined the specific expression of Ttyh1 in quiescent NSCs and niche astrocytes. Further evaluations on Ttyh1 knockout mice revealed that Ttyh1 ablation leads to activated neurogenesis and enhanced spatial learning and memory in adult mice (6–8 weeks). Correspondingly, Ttyh1 deficiency results in accelerated exhaustion of NSC pool and impaired neurogenesis in aged mice (12 months). By RNA-sequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1. Our research uncovered new endogenous mechanisms that regulate quiescence versus activation of NSCs, therefore provide novel targets for the intervention to activate quiescent NSCs to participate in injury repair during pathology and aging.
Highlights
Neural stem cells (NSCs) in the neurogenic niches of the adult mammalian brain are in different quiescent states, proliferate and generate descendant cells, which contribute to the preexisting neuronal networks and affect animal behaviors (Codega et al, 2014; Urbán et al, 2019)
By RNAsequencing, bioinformatics and molecular biological analysis, we found that Ttyh1 is involved in the regulation of calcium signaling in NSCs, and transcription factor NFATc3 is a critical effector in quiescence versus cell cycle entry regulated by Ttyh1
We found that Ttyh1 was mostly co-labeled with NSC makers such as GFAP, CD133, and Sox2, with the proportions of double positive cells in total Ttyh1+ cells as 98.68 ± 0.69%, 88.94 ± 2.16%, and 87.90 ± 3.61%, respectively, (Figures 1A,D)
Summary
Neural stem cells (NSCs) in the neurogenic niches of the adult mammalian brain are in different quiescent states, proliferate and generate descendant cells, which contribute to the preexisting neuronal networks and affect animal behaviors (Codega et al, 2014; Urbán et al, 2019). There are two main neurogenic niches in the adult mammalian brain, the subventricular zone (SVZ) adjacent to the ependyma and the subgranular zone (SGZ) of the hippocampal dentate gyrus. The identities of NSC subgroups in neurogenic niches are dynamic, with different metabolic characteristics, diverse physiological activities, and dissimilar molecular markers (Ming and Song 2011; Bond et al, 2015; Zywitza et al, 2018). It is important to find subgroup-specific molecules, which might regulate the transition between different development stages, especially from quiescence to activation
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