The metallic compound promotes primordial follicle activation and ameliorates fertility deficits in aged mice
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PROVIDER: PRJNA971656 | ENA |
REPOSITORIES: ENA
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Project description:We found MnCl2 and ZnSO4 promoted the activation of mouse primordial follicles through glycosis-dependent mTOR pathway in granulosa cells and PI3K/Akt pathway in oocytes. We further analyzed the transcriptome changes in the ovaries after MnCl2 and ZnSO4 treatments.
2023-05-27 | GSE232350 | GEO
Project description:The residual dormant primordial follicles in aged women and patients with premature ovarian insufficiency (POI) are difficult to activate in vivo. In this study, we found that PDE1A, PDE2A and PDE6D were expressed mainly in mouse primordial follicle oocytes and that PDE1A and PDE2A levels were significantly decreased during the activation of primordial follicles. The specific inhibitors of PDE1 (nimodipine), PDE2 (EHNA) and PDE5/6 (zaprinast) and the nonspecific PDE inhibitors theophylline derivatives (including aminophylline, dyphylline, enprofylline, choline theophyllinate, doxofylline, arofylline and lisofylline) activated mouse primordial follicles. These inhibitors also increased the levels of cyclic adenosine monophosphate (cAMP) and phosphorylated protein kinase B (p-Akt) in cultured mouse ovaries. Moreover, the administration of aminophylline, dyphylline and enprofylline to neonatal mice by intraperitoneal injection and to adolescent mice by oral treatment increased the number of growing follicle and the levels of p-Akt in the ovaries. Importantly, the oral administration of aminophylline increased the quantity and quality of ovulated oocytes and the number of offspring in naturally aged mice. In addition, aminophylline, dyphylline and enprofylline activated human primordial follicles and increased p-Akt levels. Thus, theophylline derivatives activate primordial follicles by increasing cAMP levels and activating the PI3K/Akt pathway, and the oral administration of aminophylline increases fertility in naturally aged female mice. As oral medications, theophylline derivatives may be used to increase fertility in aged women and patients with POI.
2024-05-30 | GSE263843 | GEO
Project description:Theophylline derivatives promote the activation of primordial follicles and ameliorate fertility deficits in naturally aged mice
| PRJNA1099590 | ENA
Project description:The dormant population of ovarian primordial follicles is determined at birth and serves as the reservoir for future female fertility. Of equal importance to fertility is the rate that primordial follicles activate and enter folliculogenesis, yet our understanding of the molecular, biochemical, and cellular processes underpinning primordial follicle activation remains limited. The survival of primordial follicles relies on the correct complement and morphology of granulosa cells, which provide signalling factors essential for oocyte and follicular survival. To investigate the contribution of granulosa cells in the primordial-to-primary follicle transition, ovaries from C57Bl/6 mice were enzymatically dissociated at two time points spanning the initial wave of primordial follicle activation. Post-natal day (PND) 1 ovaries yielded primordial granulosa cells, and PND4 ovaries yielded a mixed population of both primordial and primary granulosa cells. The comparative transcriptome of granulosa cells at these time points was generated via the Illumina NextSeq 500 system which identified 132 significantly differentially expressed transcripts. This transcriptomic dataset confirmed the expression of factors known to be involved in primordial follicle activation belonging to TGF-B and EIF4E signalling pathways, as well as novel factors linked to pathways involved in primordial follicle activation (ZFX, POD1, FRZB). This study highlights the dynamic changes in gene expression of granulosa cells during primordial follicle activation and provides evidence for a renewed focus into the Wnt signalling pathway’s role in primordial follicle activation.
2020-12-10 | GSE162927 | GEO
Project description:Female fertility is determined in part by the size and development of the primordial follicle pool. The current study investigates the role of glial cell-line derived neurotrophic factor (GDNF) in the regulation of primordial follicle development in the ovary. Ovaries from four-day old female rat pups were maintained in organ culture for ten days in the absence (control) or presence of GDNF or kit ligand/stem cell factor (KL). Ovaries treated with GDNF contained a significant increase in developing follicles, similar to that observed with KL treatment previously shown to promote follicle development. The actions of GDNF on the ovarian transcriptome were investigated with a microarray analysis. Immunohistochemical studies demonstrated that GDNF is localized to oocyte cytoplasm in follicles of all developmental stages, as well as to cumulus granulosa cells and theca cells in antral follicles. GDNF receptor alpha 1 (GFRalpha1) staining was localized to oocyte cytoplasm of primordial and primary follicles, and at reduced levels in oocytes of antral follicles. GFRalpha1 was present in mural granulosa cells of antral follicles, theca cells, and the ovarian surface epithelium. The localization studies were confirmed with molecular analysis. Microarray analysis was used to identify changes in the ovarian transcriptome and further elucidate the signaling network regulating early follicle development. Observations indicate that GDNF promotes primordial follicle development and mediates autocrine and paracrine cell-cell interactions required during folliculogenesis. In contrast to the testis, ovarian GDNF is predominantly produced by germ cells (oocytes) rather than somatic cells. Keywords: expression analysis, glial derived neurotrophic factor, follicle transition, ovary
2008-04-11 | GSE11133 | GEO
Project description:Female fertility is determined in part by the size and development of the primordial follicle pool. The current study investigates the role of glial cell-line derived neurotrophic factor (GDNF) in the regulation of primordial follicle development in the ovary. Ovaries from four-day old female rat pups were maintained in organ culture for ten days in the absence (control) or presence of GDNF or kit ligand/stem cell factor (KL). Ovaries treated with GDNF contained a significant increase in developing follicles, similar to that observed with KL treatment previously shown to promote follicle development. The actions of GDNF on the ovarian transcriptome were investigated with a microarray analysis. Immunohistochemical studies demonstrated that GDNF is localized to oocyte cytoplasm in follicles of all developmental stages, as well as to cumulus granulosa cells and theca cells in antral follicles. GDNF receptor alpha 1 (GFRalpha1) staining was localized to oocyte cytoplasm of primordial and primary follicles, and at reduced levels in oocytes of antral follicles. GFRalpha1 was present in mural granulosa cells of antral follicles, theca cells, and the ovarian surface epithelium. The localization studies were confirmed with molecular analysis. Microarray analysis was used to identify changes in the ovarian transcriptome and further elucidate the signaling network regulating early follicle development. Observations indicate that GDNF promotes primordial follicle development and mediates autocrine and paracrine cell-cell interactions required during folliculogenesis. In contrast to the testis, ovarian GDNF is predominantly produced by germ cells (oocytes) rather than somatic cells. Experiment Overall Design: RNA samples from two control groups (pooled untreated cultured ovaries) are compared to two treated groups (pooled cultured ovaries treated with GDNF)
2008-06-11 | E-GEOD-11133 | biostudies-arrayexpress
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).
2013-01-15 | E-GEOD-43464 | biostudies-arrayexpress
Project description:Neurotrophins are growth factors that are known to have a role in promoting cell survival and differentiation. The focus of the current study is to examine the role of neurotrophins in regulating ovarian primordial follicle development. Ovaries from 4-day old rats were placed into organ culture and cultured for 10 days in the absence or presence of neurotrophin-3 (NT3), brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF). Treatment of ovaries with NT3 resulted in a significant (P<0.01) increase in primordial follicle development (i.e. primordial to primary follicle transition). Treatment with BDNF at high doses of 100â250 ng/ml also significantly (P<0.01) increased primordial follicle development, but NGF had no effect. Immunohistochemical studies determined that NT3 was present in granulosa cells, interstitial tissue, and in the oocytes of primordial and primary follicles. The NT3 receptor NTRK3 was present in oocytes at all stages of development. Analysis of ovaries that contain predominantly primordial follicles demonstrated the transcripts for NT3, NTRK3, NGF, and the BDNF/neurotrophin-4 (NT4) receptor NTRK2 are expressed, while BDNF, NT4, and the NGF receptor NTRK1 are not detectable. Inhibition of the NTRK3 receptor with the tyrophostin AG 879 resulted in oocyte death and a significant (P<0.01) reduction in follicle pool size. Inhibition of the NTRK receptors with K252a slowed primordial to primary follicle transition. A microarray analysis demonstrated that a small number of genes were differentially expressed after NT3 treatment. Observations indicate that the neurotrophin NT3, acting through the NTRK3 receptor in oocytes, promotes the primordial to primary follicle transition. Reproduction (2009) 138, pp. 697-707 We used microarrays to determine genes expressed differentially between control and NT3 (neurotrophin-3) treated P4 ovary. RNA samples from 3 control groups are compared to 3 NT3 treated ovary groups.
2010-02-21 | E-GEOD-20358 | biostudies-arrayexpress
Project description:The assembly of the developmentally arrested primordial follicle and subsequent transition to the primary follicle are poorly understood processes critical to ovarian biology. Abnormal primordial follicle development can lead to pathologies such as premature ovarian failure. The current study used a genome-wide expression profile to investigate primordial follicle assembly and development. Rat ovaries with predominantly unassembled, primordial, or primary follicles were obtained. RNA from these ovaries was hybridized to rat microarray gene chips, and the gene expression (i.e., ovarian transcriptome) was compared between the developmental stages. Analysis of the ovarian transcriptome demonstrated 148 genes up-regulated and 50 genes down-regulated between the unassembled and primordial follicle stages. Observations demonstrate 80 genes up-regulated and 44 genes down-regulated between the primordial and primary follicle stages. The analysis demonstrated 2332 genes common among the three developmental stages, 146 genes specific for the unassembled follicles, 94 genes specific for the primordial follicles, and 151 genes specific for the primary follicles. Steroidogenic genes are up-regulated between unassembled and primordial follicles, and then many are again down-regulated between primordial and primary follicles. The hormones inhibin and Mullerian inhibitory substance (MIS) display a similar pattern of expression with the highest levels of mRNA in the primordial follicles. Several novel unknown genes that had dramatic changes in expression during primordial follicle development were also identified. Gene families/clusters identified that were up-regulated from unassembled to primordial follicles include growth factors and signal transduction gene clusters, whereas a down-regulated gene family was the synaptonemal complex genes associated with meiosis. Gene families/clusters that were up-regulated between primordial and primary follicles included immune response genes, metabolic enzymes, and proteases, whereas down-regulated gene families include the globulin genes and some steroidogenic genes. The expression of several growth factors changed during primordial follicle development, including vascular endothelial growth factor and insulin-like growth factor II. Elucidation of how these changes in gene expression coordinate primordial follicle assembly and the primordial to primary follicle transition provides a better understanding of these critical biological processes and allows selection of candidate regulatory factors for further investigation. Experiment Overall Design: RNA samples from two control groups (pooled untreated cultured ovaries) are compared to two treated groups (pooled cultured ovaries treated with progesterone)
2008-06-16 | E-GEOD-9300 | biostudies-arrayexpress
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.
2013-01-15 | GSE43464 | GEO