GDF9
Growth/differentiation factor 9 precursor (GDF-9)
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Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-KIT according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.
Keywords
- BMP15
- C-KIT
- GDF9
- Ovarian aging
- biomarkers
Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.
MeSH Terms
- Adipose Tissue, Brown
- Animals
- Cellular Senescence
- Female
- Longevity
- Male
- Mice
- Ovarian Follicle
- Ovary
- Rats
- Rats, Sprague-Dawley
- Transplantation, Heterologous
Keywords
- aging
- brown adipose tissue (BAT)
- lifespan
- mice
- ovary
- rat
- xenotransplant
The aim of this study was to investigate the impact of diosgenin, an important monomer of sapogenins in yams, on ovarian reserve in a natural aging mice model. This randomized controlled trial included 60 9-month-old C57 naturally aging female mice. Twenty-one mice were assigned to the dio group and were fed a single dose of diosgenin (200 mg/kg/day) suspended in 0.3% CMC. Twenty mice were assigned to the DHEA group and were fed a single dose of DHEA (1.25 mg/kg/day) suspended in 0.3% CMC. The remaining 20 mice were assigned to the old control group and were fed a single dose of 0.3% CMC. Three months later, the reproductive performance of these female mice was determined by evaluating ovarian follicles and oocyte number and quality in IVF and comparing age-matched and young controls. The impact of NOBOX, GDF9 and BMP15 mRNA expression was also evaluated. Diosgenin improves ovarian reserve in naturally aging mice in terms of increasing the number of primary follicles (P < 0.05) and serum levels of AMH (P < 0.05). Diosgenin could counteract age-associated ovarian dysfunction by improving the ovarian reserve in a natural aging mice model.
MeSH Terms
- Animals
- Anti-Mullerian Hormone
- Bone Morphogenetic Protein 15
- Diosgenin
- Female
- Growth Differentiation Factor 9
- Homeodomain Proteins
- Mice
- Mice, Inbred C57BL
- Oocytes
- Ovarian Reserve
- Ovary
- Transcription Factors
Keywords
- Aging
- Diosgenin
- Mouse model
- Ovarian reserve
We hypothesised that advanced mare age is associated with follicle and oocyte gene alterations. The aims of the study were to examine quantitative and temporal differences in mRNA for LH receptor (LHR), amphiregulin (AREG) and epiregulin (EREG) in granulosa cells, phosphodiesterase (PDE) 4D in cumulus cells and PDE3A, G-protein-coupled receptor 3 (GPR3), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and mitochondrial (mt) DNA in oocytes. Samples were collected from dominant follicles of Young (3-12 years) and Old (≥20 years) mares at 0, 6, 9 and 12h after administration of equine recombinant LH. LHR mRNA declined after 0h in Young mares, with no time effect in Old mares. For both ages, gene expression of AREG was elevated at 6 and 9h and EREG was expression was elevated at 9h, with higher expression in Old than Young mares. Cumulus cell PDE4D expression increased by 6h (Old) and 12h (Young). Oocyte GPR3 expression peaked at 9 and 12h in Young and Old mares, respectively. Expression of PDE3A increased at 6h, with the increase greater in oocytes from Old than Young mares at 6 and 9h. Mean GDF9 and BMP15 transcripts were higher in Young than Old, with a peak at 6h. Copy numbers of mtDNA did not vary over time in oocytes from Young mares, but a temporal decrease was observed in oocytes from Old mares. The results support an age-associated asynchrony in the expression of genes that are essential for follicular and oocyte maturation before ovulation.
MeSH Terms
- Aging
- Amphiregulin
- Animals
- Bone Morphogenetic Protein 15
- Cumulus Cells
- Cyclic Nucleotide Phosphodiesterases, Type 4
- DNA, Mitochondrial
- Epiregulin
- Female
- Gene Expression
- Growth Differentiation Factor 9
- Horses
- Oocytes
- Ovarian Follicle
- Receptors, LH
- Transcriptome
Do any mutations in growth differentiation factor 9 (GDF9) have a role in diminished ovarian reserve (DOR) in young women? The GDF9 p.R146C mutation may be a source of DOR in some young women. DOR affects 10% of women under 37 years of age and is associated with accelerated expenditure of follicles. GDF9 is an oocyte-secreted factor that plays a critical role in follicular development and female fertility. Several GDF9 variants have been linked to ovarian dysfunction. This case-control study included 139 women with DOR and 152 controls aged under 37 years. All women were recruited in a Chinese tertiary center and underwent DNA sequencing of GDF9 gene. We then determined the molecular and biological properties of mutant GDF9 proteins using protein expression, structural prediction and functional analyses. We identified two mutations in the proregion of GDF9 gene: c.169T > G (p.D57Y) and c.436T > C (p.R146C). The p.R146C mutation was found in three women with DOR but was absent in the control population. This mutation was also associated with significant reductions in GDF9 mature protein secretion in cultured cells. Functional studies with human granulosa cells (GCs) showed that the p.R146C mutation reduced the abilities of GDF9 to stimulate GC proliferation and to activate the Smad2 pathway. Protein structure modeling predicted that p.R146C disrupted an α-helix in GDF9 protein. In contrast with p.R146C, the p.D57Y mutation, found in both the DOR and control groups (6 versus 2), had no obvious deleterious effects. Larger studies in varying populations may validate the role of GDF9 mutation in young women with DOR. These results may provide new insights into the pathophysiological mechanisms of early-onset DOR.
MeSH Terms
- Adult
- Amino Acid Substitution
- Asian Continental Ancestry Group
- Case-Control Studies
- Cell Proliferation
- Cells, Cultured
- China
- Cohort Studies
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Granulosa Cells
- Growth Differentiation Factor 9
- HEK293 Cells
- Humans
- Mutation
- Primary Ovarian Insufficiency
- Protein Conformation
- Protein Precursors
- Recombinant Proteins
- Signal Transduction
- Smad2 Protein
Keywords
- GDF9
- diminished ovarian reserve
- folliculogenesis
- mutation
- reproductive aging