The Role of Oocyte‐Secreted Factors <i>GDF9</i> and <i>BMP15</i> in Follicular Development and Oogenesis

Paulini, Fernanda; Melo, E. O.

doi:10.1111/j.1439-0531.2010.01739.x

Cited by 142 publications

(112 citation statements)

References 117 publications

(264 reference statements)

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“…Several growth factor and receptor mRNAs that were differentially expressed in F3 generation vinclozolin or DDT lineage granulosa cells have been previously implicated in normal ovarian function (Kitlg, Bmp15, GDF9, Pdgfra) [44–47]. In addition, abnormalities in Gdf9 and BMP15 expression are associated with polycystic ovarian syndrome (PCOS) and primary ovarian insufficiency (POI) in humans [48–50].…”

Section: Discussionmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). Previous studies have shown that exposure to a number of environmental toxicants can promote the epigenetic transgenerational inheritance of ovarian disease. In the current study, transgenerational changes to the transcriptome and epigenome of ovarian granulosa cells are characterized in F3 generation rats after ancestral vinclozolin or DDT exposures. In purified granulosa cells from 20-day-old F3 generation females, 164 differentially methylated regions (DMRs) (P < 1 x 10−6) were found in the F3 generation vinclozolin lineage and 293 DMRs (P < 1 x 10−6) in the DDT lineage, compared to controls. Long noncoding RNAs (lncRNAs) and small noncoding RNAs (sncRNAs) were found to be differentially expressed in both the vinclozolin and DDT lineage granulosa cells. There were 492 sncRNAs (P < 1 x 10−4) in the vinclozolin lineage and 1,085 sncRNAs (P < 1 x 10−4) in the DDT lineage. There were 123 lncRNAs and 51 lncRNAs in the vinclozolin and DDT lineages, respectively (P < 1 x 10−4). Differentially expressed mRNAs were also found in the vinclozolin lineage (174 mRNAs at P < 1 x 10−4) and the DDT lineage (212 mRNAs at P < 1 x 10−4) granulosa cells. Comparisons with known ovarian disease associated genes were made. These transgenerational epigenetic changes appear to contribute to the dysregulation of the ovary and disease susceptibility that can occur in later life. Observations suggest that ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.

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Section: Discussionmentioning

confidence: 99%

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

et al. 2018

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“…BMP15 is a growth factor specifically secreted from oocytes, which is important for promoting follicular development (13)(14)(15)(16)(17)(18). GC is one of the target cells of BMP15 (19,20). Otsuka et al (43) demonstrated that BMP15 controls the expression of plasma protein-A in granulose cells coordinating with follicle stimulating hormone, guaranteeing the development of the advantage follicle.…”

Section: Discussionmentioning

confidence: 99%

“…BMP15 is specifically expressed in oocytes and is important for the regulation of cell growth, development and apoptosis (19,20). FoxO3a can bind the BMP15 gene promoter to regulate its expression.…”

Section: Hfd-induced Obesity Suppresses the Phosphorylation Level Ofmentioning

confidence: 99%

“…Bone morphogenetic protein 15 (BMP15) and the transforming growth factor-β family members, are fundamental for the paracrine signaling between oocytes and GCs that controls follicular development and cumulus expansion (13)(14)(15)(16)(17)(18). GCs are one of the target cells of BMP15 (19,20). BMPs bind to their cell membrane receptor and exert their effects through receptor-mediated activation of Smad transcription factors (21).…”

Section: Introductionmentioning

confidence: 99%

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Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Zhang

Liao

et al. 2016

Molecular Medicine Reports

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Abstract. Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity-induced infertility is not yet clear. The present study established a high-fat diet (HFD)-induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD-induced obesity on follicular development in the mouse ovary. The 4-week-old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time-dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD-induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time-dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.

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“…As only the mature GDF9 peptide is deemed biologically active (Paulini & Melo, 2011), mutations that are located proximal to the RRHR furin protease cleavage site (proximal to amino acid position 318) are regarded as not affecting the protein function (Hanrahan et al, 2004). A single non-synonymous SNP in exon 1 (c.260G>A) is located before the furin cleavage site, and causes only a conservative substitution of amino acids (Arg87His) (Hanrahan et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Growth differentiation factor 9 gene variants in Sudanese desert sheep ecotypes

et al. 2016

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Certain variants in the growth differentiation factor 9 (GDF9) gene have major effects on the ovulation rate in sheep. The aim of this study was to analyse GDF9 variability in the Sudanese desert sheep ecotypes Ashgar, Dubasi and Watish, and to test identified variants for association with litter size. For this purpose, ewes of these ecotypes with litter size records for at least two litters were sampled. The complete GDF9 exon 2 was sequenced in a total of 28 ewes. An additional variant in exon 1 (c260G>A) was genotyped by restriction-length polymorphism analysis in 97 ewes. Differences in genotype and allele frequencies of polymorphic positions between two groups differing in litter size (only a single lamb versus more than a single lamb) were tested for significance using Fisher's exact test. GDF9 exon 2 variants c.477G>A and c.721G>A and exon 1 variant c.260G>A were found to be polymorphic in all three sheep ecotypes. Exon 2 variants c.471C>T and c.978 A>G were polymorphic in at least one ecotype. No significant associations were observed between allele and genotype frequencies of identified variants and litter size. This suggests that GDF9 variants influencing ovulation are absent in these Sudanese sheep ecotypes, and therefore cannot be used to increase litter size within this population of sheep. ______________________________________________________________________________________

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The Role of Oocyte‐Secreted Factors GDF9 and BMP15 in Follicular Development and Oogenesis

Cited by 142 publications

References 117 publications

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Growth differentiation factor 9 gene variants in Sudanese desert sheep ecotypes

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