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Inhibition of integrated stress response promotes primordial follicle activation via the mTOR pathway

ABSTRACT: Background: The integrated stress response (ISR) is a conserved signaling network that enables cells to cope with stress and maintain homeostasis. Accumulating evidence from both human and animal studies suggests that chronic stress has been implicated as a significant factor in the development of premature ovarian insufficiency (POI). The aim of this study was to investigate the effects of targeted ISR inhibition by ISRIB on primordial follicle activation and explore its underlying mechanisms in a mouse model. Methods: This study used intraperitoneal injection to investigate the effects of ISR activity and its inhibitor ISRIB on primordial follicle activation in vivo. Newborn ICR mice were randomly assigned to the Control, Corticosterone, ISRIB, and Corticosterone + ISRIB groups. Mouse and human ovarian tissues were cultured in vitro and treated with ISRIB and/or a proto-oncogenic receptor tyrosine kinase (KIT) inhibitor. Various methods were used to assess differences in follicle counting, ISR activity, cell proliferation, cell apoptosis, and the mTOR pathway. Results: ISR activity was present in normal newborn mouse ovaries and significantly increased in corticosterone-induced stress mouse ovaries. Excessive ISR activity induced by corticosterone reduced the number of primordial follicles, which could be partially reversed by ISRIB. In vitro treatment with ISRIB inhibited the protein levels of p-eIF2α and ATF4, while promoting granulosa cell proliferation and primordial follicle activation, and increasing the levels of phosphorylated mTOR (p-mTOR), phosphorylated protein kinase B (p-Akt), and KIT ligand (KITL). The KIT inhibitor ISCK03 significantly decreased the phosphorylation levels of Akt and forkhead box O3a (FOXO3a), as well as the number of growing follicles induced by ISRIB. In both in vivo injection and in vitro ovarian tissue culture models, ISRIB promoted primordial follicle activation via the mTOR pathway in pre-granulosa cells. Conclusion: The results suggest that inhibiting ISR can prevent primordial follicle depletion caused by excessive ISR activity. ISRIB has been shown to promote primordial follicle activation in mouse and human ovaries via the mTOR pathway. These results suggest that ISRIB may be a potential therapeutic option for infertility in stress-induced POI patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE284367 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Primordial follicle assembly is the process by which ovarian primordial follicles are formed. During follicle assembly oocyte nests break down and a layer of pre-granulosa cells surrounds individual oocytes to form primordial follicles. The pool of primordial follicles formed is the source of oocytes for ovulation during a femaleM-bM-^@M-^Ys reproductive life. Complex networks of cellular signaling and gene expression are essential for any biological process. A systems biology experimental approach provides a global view of these gene relationships in a particular developmental process. The current study utilized a systems approach to detect all genes that are differentially expressed in response to seven different growth factor and hormone treatments known to influence primordial follicle assembly in a neonatal rat ovary culture system. One novel growth factor, basic fibroblast growth factor (FGF2), was experimentally determined to inhibit follicle assembly. The different growth factor and hormone treatments were all found to affect the same physiological pathways, but each treatment affected a unique set of differentially expressed genes (signature gene set). A gene bionetwork analysis identified gene modules of coordinately expressed interconnected genes and it was found that different gene modules appear to accomplish distinct tasks during primordial follicle assembly. Unique gene networks were identified for a number of the modules and signature gene sets. Predictions of physiological pathways important to follicle assembly were validated using ovary culture experiments in which ERK1/2 (MAPK1) activity was increased. A number of the highly interconnected genes in these gene networks have previously been linked to primary ovarian insufficiency (POI) and polycystic ovarian disease syndrome (PCOS). Observations have identified novel factors and gene networks that regulate primordial follicle assembly. This systems approach has helped elucidate the molecular control of primordial follicle assembly and provided potential therapeutic targets for the treatment of ovarian disease. We used microarrays to determine genes expressed differentially between control and P0 ovaries treated with 7 growth factors: AMH, CTGF, estradiol (E2), Activin-a, FGF2, progesterone (P4), and TNFa. RNA samples from 7 control samples are compared to 3 growth factor treated ovary samples for each AMH (human Anti-MM-CM-<lerian hormone), CTGF (connective tissue growth factor ), estradiol (E2), TNF (tumor necrosis factor ), FGF2 (fibroblast growth factor 2), Inhba (inhibin, beta A), and 2 samples for progesterone (P4).

Project description:Primordial follicle assembly is the process by which ovarian primordial follicles are formed. During follicle assembly oocyte nests break down and a layer of pre-granulosa cells surrounds individual oocytes to form primordial follicles. The pool of primordial follicles formed is the source of oocytes for ovulation during a female’s reproductive life. Complex networks of cellular signaling and gene expression are essential for any biological process. A systems biology experimental approach provides a global view of these gene relationships in a particular developmental process. The current study utilized a systems approach to detect all genes that are differentially expressed in response to seven different growth factor and hormone treatments known to influence primordial follicle assembly in a neonatal rat ovary culture system. One novel growth factor, basic fibroblast growth factor (FGF2), was experimentally determined to inhibit follicle assembly. The different growth factor and hormone treatments were all found to affect the same physiological pathways, but each treatment affected a unique set of differentially expressed genes (signature gene set). A gene bionetwork analysis identified gene modules of coordinately expressed interconnected genes and it was found that different gene modules appear to accomplish distinct tasks during primordial follicle assembly. Unique gene networks were identified for a number of the modules and signature gene sets. Predictions of physiological pathways important to follicle assembly were validated using ovary culture experiments in which ERK1/2 (MAPK1) activity was increased. A number of the highly interconnected genes in these gene networks have previously been linked to primary ovarian insufficiency (POI) and polycystic ovarian disease syndrome (PCOS). Observations have identified novel factors and gene networks that regulate primordial follicle assembly. This systems approach has helped elucidate the molecular control of primordial follicle assembly and provided potential therapeutic targets for the treatment of ovarian disease. We used microarrays to determine genes expressed differentially between control and P0 ovaries treated with 7 growth factors: AMH, CTGF, estradiol (E2), Activin-a, FGF2, progesterone (P4), and TNFa.

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Inhibition of integrated stress response promotes primordial follicle activation via the mTOR pathway

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