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Chronic stress induces neural stem cell quiescence in the hippocampus by repressing Ascl1 expression [CUT&Tag]

ABSTRACT: Chronic stress inhibits neurogenesis, yet its impact on neural stem cells (NSCs) remains poorly understood. Here, using the 5-bromo-2′-deoxyuridine (BrdU) label-retaining assay, we found that chronic restraint stress (CRS) in adult mice promoted quiescence in hippocampal NSCs (i.e. radial-glial-like cells, RGLs). Long-term administration of the synthetic stress hormone agonist dexamethasone (Dex) to adult mice recapitulated the phenotype. Moreover, pre-administration of the antagonist mifepristone (RU486) prevented RGLs from quiescence. At the cellular level, Dex induced reversible quiescence in hippocampal NSCs (HpNSCs) in a manner similar to the quiescence-promoting signal BMP4 in vitro. However, Dex and BMP4 regulated overlapping yet distinct NSC quiescence programs, with their co-regulation primarily being synergistic. Mechanistically, Dex downregulated the expression of achaete-scute homolog 1 (Ascl1) by repressing a distal enhancer. These data suggest that chronic stress induces quiescence in RGLs by repressing the transcription of the quiescence regulator gene Ascl1, and that synthetic glucocorticoid antagonists may have therapeutic value in correcting abnormalities of NSC activity in conditions associated with elevated cortisol levels, including psychological and mental health conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE262991 | GEO | 2026/03/20

REPOSITORIES: GEO

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Project description:Adult radial glia-like cells (RGLs) residing in the subgranular zone (SGZ) of the dentate gyrus (DG) are finely regulated to control the generation of new neurons. Quiescence is essential for the long-term maintenance of the RGL pool. Intrinsic factors as well as extrinsic niche signals orchestrate the balance between RGL quiescence and activation, but the mechanisms are still not completely understood. Yap1, a core factor of Hippo signaling, is very important for the proliferation of stem cells of various organs and species, such as intestinal stem cells of the mouse and neural stem cells in Drosophila brain. Here I addressed the role of Yap1 in adult hippocampal neurogenesis by gain- and loss-of-function studies. I found that the expression of Yap1 was enriched in adult RGLs, but was undetectable in other cell types such as neurons and cells of the oligodendroglial lineage. Through the analysis of conditional knock-out of Yap1 in adult RGLs and their lineage, I found that fewer RGLs became activated while a significantly higher proportion of RGLs remained in the quiescent state. Conversely, overexpression of constitutively active mutant variant of Yap1 (Yap1 5SA) induced the proliferation of quiescent RGLs in vitro and in vivo. This effect was dependent on functional interaction with the TEA Domain Transcription Factor (TEAD). Pharmacological blocking the interaction between endogenous Yap1 and TEAD by verteporfin reduced the rate of proliferation of neural progenitors in vitro, which indicates a physiological role of Yap1-TEAD interaction in regulating the transition between quiescence and activation. Interestingly, constitutive expression of Yap1 5SA in RGLs blocked adult neurogenesis and retained the cells in a progenitor-like (Sox2+) state. To further explore the molecular mechanisms of Yap1 in regulating the activation of quiescent RGLs, single-cell RNA sequencing analysis was performed at 3 and 7 days following Yap1 5SA overexpression. Yap1 5SA overexpressing cells exhibited increased signature of active NSCs but also displayed distinct features such as epithelial-to-mesenchymal transition (EMT). Importantly, we found that Catenin Beta 1 (CTNNB1) was upregulated suggesting a potential involvement of Wnt signaling in the proliferative effect of Yap1 5SA overexpression in adult NSCs. In sum, this work provides compelling evidence for regulation of the balance between activation and quiescence of adult hippocampal RGLs by Yap1.

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Chronic stress induces neural stem cell quiescence in the hippocampus by repressing Ascl1 expression [CUT&Tag]

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