The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles

Zhao, Peikun; Song, Zidai; Wang, Yan; Cai, Han; Du, Xiaoyan; Li, Changlong; Lv, Jing; Liu, Xin; Guo, Meng; Chen, Zhenwen

doi:10.18632/aging.202235

Cited by 5 publications

(7 citation statements)

References 61 publications

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“… 38 Moreover, during primordial follicle development, FBXW7 inhibits primordial follicle activation via the eNOS/cGMP/PKG pathway. 39 These researches demonstrate the vital regulatory role of FBXW7 in cell cycle, particularly in the germ cell cycle, which corroborates our findings. For the first time, our experiments demonstrated the association between normal FBXW7 function with folliculogenesis and ovarian function, and its dysfunction is largely implicated in POI, thus reinforcing our initial hypothesis.…”

Section: Discussionsupporting

confidence: 89%

“…Similarly, in the nematode Caenorhabditis elegans, the FBXW7 homologue SEL‐10 coordinates meiosis and post‐transcriptional gene expression during gametogenesis through the MPK‐1/MAPK pathway 38 . Moreover, during primordial follicle development, FBXW7 inhibits primordial follicle activation via the eNOS/cGMP/PKG pathway 39 . These researches demonstrate the vital regulatory role of FBXW7 in cell cycle, particularly in the germ cell cycle, which corroborates our findings.…”

Section: Discussionsupporting

confidence: 87%

“…38 Moreover, during primordial follicle development, FBXW7 inhibits primordial follicle activation via the eNOS/cGMP/PKG pathway. 39 These researches demonstrate the vital regulatory role of FBXW7 in cell cycle, particularly in the germ cell cycle, which corroborates that the occurrence of POI is not directly linked to decreased FBXW7 expression in GCs. Therefore, we reasoned that oocytes regulate the functions of GCs through downstream factors shared with GCs, which is probably modulated by FBXW7.…”

Section: Discussionsupporting

confidence: 59%

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Deletion of Fbxw7 in oocytes causes follicle loss and premature ovarian insufficiency in mice

Zhao,

Zhang,

Zhou

et al. 2024

J Cellular Molecular Medi

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Premature ovarian insufficiency (POI) is one of the important causes of female infertility. Yet the aetiology for POI is still elusive. FBXW7 (F‐box with 7 tandem WD) is one of the important components of the Skp1‐Cullin1‐F‐box (SCF) E3 ubiquitin ligase. FBXW7 can regulate cell growth, survival and pluripotency through mediating ubiquitylation and degradation of target proteins via triggering the ubiquitin‐proteasome system, and is associated with tumorigenesis, haematopoiesis and testis development. However, evidence establishing the function of FBXW7 in ovary is still lacking. Here, we showed that FBXW7 protein level was significantly decreased in the ovaries of the cisplatin‐induced POI mouse model. We further showed that mice with oocyte‐specific deletion of Fbxw7 demonstrated POI, characterized with folliculogenic defects, early depletion of follicle reserve, disordered hormonal secretion, ovarian dysfunction and female infertility. Impaired oocyte‐GCs communication, manifested as down‐regulation of connexin 37, may contribute to follicular development failure in the Fbxw7‐mutant mice. Furthermore, single‐cell RNA sequencing and in situ hybridization results indicated an accumulation of Clu and Ccl2 transcripts, which may alter follicle microenvironment deleterious to oocyte development and accelerate POI. Our results establish the important role of Fbxw7 in folliculogenesis and ovarian function, and might provide valuable information for understanding POI and female infertility.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 87%

“…38 Moreover, during primordial follicle development, FBXW7 inhibits primordial follicle activation via the eNOS/cGMP/PKG pathway. 39 These researches demonstrate the vital regulatory role of FBXW7 in cell cycle, particularly in the germ cell cycle, which corroborates that the occurrence of POI is not directly linked to decreased FBXW7 expression in GCs. Therefore, we reasoned that oocytes regulate the functions of GCs through downstream factors shared with GCs, which is probably modulated by FBXW7.…”

Section: Discussionsupporting

confidence: 59%

See 1 more Smart Citation

Deletion of Fbxw7 in oocytes causes follicle loss and premature ovarian insufficiency in mice

Zhao,

Zhang,

Zhou

et al. 2024

J Cellular Molecular Medi

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“…Though the functional significance of PPP in primary and later follicle stages has not been elucidated, PPP-mediated nucleotide biosynthesis may be required for oocyte growth. A further study revealed that NOS in primordial oocytes and pre-granulosa cells synthesized NO, which activates cGMP-PKG signaling and subsequently downregulates an E3 ubiquitin ligase, F-box and WD repeat domain containing 7, FBXW7, resulting in the stabilization of mTOR in pregranulosa cells [Zhao et al, 2020]. This process activates KITL expression in pre-granulosa cells, triggers the transduction of KITL/KIT/PI3K/AKT/FOXO3a signaling in oocytes, and consequently promotes primordial follicule activation, oocyte growth, and granulosa cell proliferation in neonatal ovaries.…”

Section: Metabolism In Oogenesismentioning

confidence: 99%

Metabolic Control of Germline Formation and Differentiation in Mammals

Hayashi

Matsui

2022

Sex Dev

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Background: The germ cell lineage involves dynamic epigenetic changes during its formation and differentiation that are completely different from those of the somatic cell lineage. Metabolites and metabolic pathways have been reported as key factors related to the regulation of epigenetics as cofactors and substrates. However, our knowledge about the metabolic characteristics of germ cells, especially during the fetal stage, and their transition during differentiation is quite limited due to the rarity of the cells. Nevertheless, recent developments in omics technologies have made it possible to extract comprehensive metabolomic features of germ cells. Summary: In this review, we present the latest researches on the metabolic properties of germ cells in 4 stages: primordial germ cell specification, fetal germ cell differentiation, spermatogenesis, and oogenesis. At every stage, extensive published data has been accumulated on energy metabolism, and it is possible to describe its changes during germ cell differentiation in detail. As pluripotent stem cells differentiate into germ cells, energy metabolism shifts from glycolysis to oxidative phosphorylation; however, in spermatogenesis, glycolytic pathways are also temporarily dominant in spermatogonial stem cells. Although the significance of metabolic pathways other than energy metabolism in germ cell differentiation is largely unknown, the relation of the pentose phosphate pathway and Ser-Gly-one-carbon metabolism with germ cell properties has been suggested at various stages. We further discuss the relationship between these characteristic metabolic pathways and epigenetic regulation during germ cell specification and differentiation. Finally, the relevance of dietary and supplemental interventions on germ cell function and epigenomic regulation is also discussed. Key Messages: Comprehensive elucidation of metabolic features and metabolism-epigenome crosstalk in germ cells is important to reveal how the characteristic metabolic pathways are involved in the germ cell regulation. The accumulation of such insights would lead to suggestions for optimal diets and supplements to maintain reproductive health through modulating metabolic and epigenetic status of germ cells.

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“…This again supported that cfRNAs could be used to predict different-sized follicles’ follicular fluid. Previous studies have shown that cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase G (PKG) were expressed in neonatal ovaries of pre-granulosa cells, promoting primordial follicle activation, oocyte growth, and granulosa cell proliferation ( Tian et al, 2018 ; Zhao et al, 2020 ). This study found that the cGMP-PKG signaling pathway was significantly enriched, which indicated that the activation of the cGMP-PKG signaling pathway may be closely related to the development of follicles.…”

Section: Discussionmentioning

confidence: 99%

Extracellular cell-free RNA profile in human large follicles and small follicles

Shi

Pan

Sheng

et al. 2022

Front. Cell Dev. Biol.

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Background: Previous studies have shown that a large number of valuable and functional cell-free RNAs (cfRNAs) were found in follicular fluid. However, the species and characteristics of follicular fluid cfRNAs have not been reported. Furthermore, their implications are still barely understood in the evaluation of follicular fluid from follicles of different sizes, which warrants further studies.Objective: This study investigated the landscape and characteristics of follicular fluid cfRNAs, the source of organization, and the potential for distinguishing between follicles of different sizes.Methods: Twenty-four follicular fluid samples were collected from 20 patients who received in vitro fertilization (n = 9) or ICSI (n = 11), including 16 large follicular fluid and 8 small follicular fluid samples. Also, the cfRNA profile of follicular fluid samples was analyzed by RNA sequencing.Results: This result indicated that the concentration of follicular fluid cfRNAs ranged from 0.78 to 8.76 ng/ml, and fragment length was 20–200 nucleotides. The concentration and fragment length of large follicular fluid and small follicular fluid samples were not significantly different (p > 0.05). The technical replica correlation of follicular fluid samples ranged from 0.3 to 0.9, and the correlation of small follicular fluid samples was remarkably (p < 0.001) lower than that of large follicular fluid samples. Moreover, this study found that cfRNAs of the follicular fluid could be divided into 37 Ensembl RNA biotypes, and a large number of mRNAs, circRNAs, and lncRNAs were observed in the follicular fluid. The number of cfRNAs in large follicular fluid was remarkably (p < 0.05) higher than that of small follicular fluid. Furthermore, the follicular fluid contained a large amount of intact mRNA and splice junctions and a large number of tissue-derived RNAs, which are at a balanced state of supply and elimination in the follicular fluid. KEGG pathway analysis showed that differentially expressed cfRNAs were enriched in several pathways, including thyroid hormone synthesis, the cGMP-PKG signaling pathway, and inflammatory mediator regulation of TRP channels. In addition, we further showed that four cfRNAs (TK2, AHDC1, PHF21A, and TTYH1) serve as a potential indicator to distinguish the follicles of different sizes. The ROC curve shows great potential to predict follicular fluid from follicles of different sizes [area under the curve (AUC) > 0.88].Conclusion: Overall, our study revealed that a large number of cfRNAs could be detected in follicular fluid and could serve as a potential non-invasive biomarker in distinguishing between follicles of different sizes. These results may inform the study of the utility and implementation of cfRNAs in clinical practice.

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The endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase G pathway activates primordial follicles

Cited by 5 publications

References 61 publications

Deletion of Fbxw7 in oocytes causes follicle loss and premature ovarian insufficiency in mice

Deletion of Fbxw7 in oocytes causes follicle loss and premature ovarian insufficiency in mice

Metabolic Control of Germline Formation and Differentiation in Mammals

Extracellular cell-free RNA profile in human large follicles and small follicles

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