ArticleCell communication and signaling : CCS2024
SFRP4 promotes autophagy and blunts FSH responsiveness through inhibition of AKT signaling in ovarian granulosa cells.
Article in Cell communication and signaling : CCS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- GSK3β inhibits the differentiation of follicular granulosa cells by promoting lipid accumulation through autophagy in chickens.Poultry science · 2026Article
- Single-cell atlas of reproductive endocrine organs reveals transcriptomic responses to type 1 diabetes mellitus in nonhuman primates.Cell discovery · 2026Article
- Autophagy in ovary: protective roles, pathological consequences, and unresolved issues.Journal of ovarian research · 2025Review
- Primary human ovarian interstitial cells contribute to murine follicle growth through follicle-interstitial paracrine crosstalk.Research square · 2025Article
- Sustained YAP1 signaling alters the fates of lutein and Müllerian mesenchymal cells in mice.Reproduction (Cambridge, England) · 2025Article
- Ramulus mori (Sangzhi) alkaloids improve intestinal oxidative damage and inflammation in DHEA-induced polycystic ovary syndrome rats via gut microbiota and metabolite modulation.Frontiers in pharmacology · 2025Article
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Abstract
backgroundSecreted frizzled-related proteins (SFRPs) comprise a family of WNT signaling antagonists whose roles in the ovary are poorly understood. Sfrp4-null mice were previously found to be hyperfertile due to an enhanced granulosa cell response to gonadotropins, leading to decreased antral follicle atresia and enhanced ovulation rates. The present study aimed to elucidate the mechanisms whereby SFRP4 antagonizes FSH action.
methodsPrimary cultures of granulosa cells from wild-type mice were treated with FSH and/or SFRP4, and effects of treatment on gene expression were evaluated by RT-qPCR and RNAseq. Bioinformatic analyses were conducted to analyse the effects of SFRP4 on the transcriptome, and compare them to those of FSH or a constitutively active mutant of FOXO1. Additional granulosa cell cultures from wild-type or Sfrp4-null mice, some pretreated with pharmacologic inhibitors of specific signaling effectors, were used to examine the effects of FSH and/or SFRP4 on signaling pathways, autophagy and apoptosis by western blotting and TUNEL.
resultsTreatment of cultured granulosa cells with recombinant SFRP4 was found to decrease basal and FSH-stimulated mRNA levels of FSH target genes. Unexpectedly, this effect was found to occur neither via a canonical (CTNNB1-dependent) nor non-canonical WNT signaling mechanism, but was found to be GSK3β-dependent. Rather, SFRP4 was found to antognize AKT activity via a mechanism involving AMPK. This lead to the hypophosphorylation of FOXO1 and a decrease in the expression of a portion of the FSH and FOXO1 transcriptomes. Conversely, FSH-stimulated AMPK, AKT and FOXO1 phosphorylation levels were found to be increased in the granulosa cells of Sfrp4-null mice relative to wild-type controls. SFRP4 treatement of granulosa cells also induced autophagy by signaling via AKT-mTORC1-ULK1, as well as apoptosis.
conclusionsThis study identifies a novel GSK3β-AMPK-AKT signaling mechanism through which SFPR4 antagonizes FSH action, and further identifies SFRP4 as a novel regulator of granulosa cell autophagy. These findings provide a mechanistic basis for the phenotypic changes previously observed in Sfrp4-null mice, and broaden our understanding of the physiological roles of WNT signaling processes in the ovary.
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