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Transcriptional signature of progesterone-induced germinal vesicle breakdown in the fathead minnow ovary (Pimephales promelas)

ABSTRACT: A growing number of studies have examined transcriptional responses to sex steroids along the hypothalamic-pituitary-gonadal axis in teleost fishes. However, data is are lacking on the molecular signaling cascades that underlie progesterone signaling. The objectives of the present study were to characterize the transcriptional response in the ovary of fathead minnow (Pimephales promelas) (FHM) in response to progesterone (P4) using transcriptomics. Female FHM ovaries were exposed in vitro to 500 ng P4/L. Germinal vesicle migration and breakdown (GVBD) was observed and microarrays were used to identify gene cascades affected by P4. Microarray analysis identified 1,265 differentially expressed transcripts after P4 treatment (p < 0.05). Functional enrichment analysis revealed that transcripts involved in the molecular functions of protein serine/threonine kinase activity, ATP binding, and activity of calcium channels were increased in the female ovary after P4 treatment. There was an overwhelming response of genes involved in structural constituent of ribosome to bethat were down-regulated with P4. There was also evidence for gene changes in steroid and maturation-related transcripts. Pathway analyses identified cell cycle regulation, insulin action, hedgehog, and B cell activation as pathways containing an over-representation of highly regulated transcripts. Significant regulatory sub-networks of P4-mediated transcripts included genes regulated by tumor protein p53 and E2F transcription factor 1, suggesting that downstream expression targets of these two proteins may be preferentially involved in P4-mediated GVBD. These data provide novel insight into the molecular signaling cascades that may underlie P4-signaling in the ovary and identifies genes and processes that may indicate premature GVBD due to environmental pollutants that mimic progestins.

ORGANISM(S): Pimephales promelas

PROVIDER: GSE43601 | GEO | 2013/07/19

SECONDARY ACCESSION(S): PRJNA186798

REPOSITORIES: GEO

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Project description:Follicle assembly is the process by which groups or ‘nests’ of oocytes break down to form primordial follicles. The size of the primordial follicle pool is the major determinant of the reproductive lifespan of a female. Previously, progesterone (P4) has been shown to inhibit follicle assembly, while tumor necrosis factor alpha (TNF-alpha) has been shown to promote the apoptosis that is necessary for follicle assembly. The current study examines how TNF-alpha and progesterone interact to regulate primordial follicle assembly. Ovaries were collected from newborn rats and placed in organ culture to examine the actions of P4 and TNF-alpha. P4 was found to decrease primordial follicle assembly and increase the percentage of un-assembled oocytes both in vitro and in vivo. TNF-alpha treatment did not change the proportion of assembled follicles in cultured ovaries, but did block the ability of P4 to inhibit follicle assembly. Microarray analysis of the ovarian transcriptome revealed that progesterone treatment of the ovaries altered the expression of 513 genes with 132 only expressed after P4 treatment and 16 only expressed in control ovaries. The majority of genes were up-regulated greater than 2-fold over control, with a small subset of 16 genes down-regulated. Categories of genes affected by P4 are described including a group of extra-cellular signaling factors. The progesterone receptors expressed at the time of follicle assembly included the surface membrane progesterone receptors PGRMC1, PGRMC2 and RDA288. The nuclear genomic P4 receptor was not expressed at appreciable levels. Progesterone increased the expression of several genes (TANK, NFkappaB, Bcl2l1 and Bcl2l2) involved in a signaling pathway that promotes cell survival and inhibits apoptosis. Observations indicate that P4 acts through the surface membrane progesterone receptors to regulate primordial follicle assembly, and that TNF-alpha can over-ride the inhibitory actions of P4 on follicle assembly. A major mechanism involved in the actions of P4 is an increase in cell survival genes and inhibition of the apoptosis pathway. Observations provide insight into the hormonal regulation of primordial follicle assembly and lead to novel approaches to potentially manipulate follicle assembly and reproductive capacity. Keywords: expression analysis, progesterone, TNFa, follicle assembly, ovary

Project description:Follicle assembly is the process by which groups or ânestsâ of oocytes break down to form primordial follicles. The size of the primordial follicle pool is the major determinant of the reproductive lifespan of a female. Previously, progesterone (P4) has been shown to inhibit follicle assembly, while tumor necrosis factor alpha (TNF-alpha) has been shown to promote the apoptosis that is necessary for follicle assembly. The current study examines how TNF-alpha and progesterone interact to regulate primordial follicle assembly. Ovaries were collected from newborn rats and placed in organ culture to examine the actions of P4 and TNF-alpha. P4 was found to decrease primordial follicle assembly and increase the percentage of un-assembled oocytes both in vitro and in vivo. TNF-alpha treatment did not change the proportion of assembled follicles in cultured ovaries, but did block the ability of P4 to inhibit follicle assembly. Microarray analysis of the ovarian transcriptome revealed that progesterone treatment of the ovaries altered the expression of 513 genes with 132 only expressed after P4 treatment and 16 only expressed in control ovaries. The majority of genes were up-regulated greater than 2-fold over control, with a small subset of 16 genes down-regulated. Categories of genes affected by P4 are described including a group of extra-cellular signaling factors. The progesterone receptors expressed at the time of follicle assembly included the surface membrane progesterone receptors PGRMC1, PGRMC2 and RDA288. The nuclear genomic P4 receptor was not expressed at appreciable levels. Progesterone increased the expression of several genes (TANK, NFkappaB, Bcl2l1 and Bcl2l2) involved in a signaling pathway that promotes cell survival and inhibits apoptosis. Observations indicate that P4 acts through the surface membrane progesterone receptors to regulate primordial follicle assembly, and that TNF-alpha can over-ride the inhibitory actions of P4 on follicle assembly. A major mechanism involved in the actions of P4 is an increase in cell survival genes and inhibition of the apoptosis pathway. Observations provide insight into the hormonal regulation of primordial follicle assembly and lead to novel approaches to potentially manipulate follicle assembly and reproductive capacity. 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)

Project description:Background: Follicular growth and maturation in semi-synchronously spawning fish involve numerous cell signaling cascades and different molecular cascades are activated or inhibited during specific stages of oocyte development. The objectives of the current study were to identify molecular pathways and temporal gene expression patterns throughout a complete breeding cycle in female wild LMB to characterize the molecular sequence of events underlying follicle and ovary development. Methods: Microarray analysis was performed on eight morphologically distinct stages, from primary stages of oocyte growth to ovulation and atresia. Ovarian tissue histology, plasma vitellogenin, and sex steroids (E2 and T) were also measured to correlate molecular signaling cascades to higher levels of biological organization. Results: Global expression patterns revealed dramatic differences between early and late stages of ovarian follicle progression, with over 200 and 500 genes being differentially expressed during both ovulation and atresia respectively (p < 0.01). Time course analysis for all stages leading to ovulation and atresia identified increased expression of GABAA receptor subunits and peroxisome proliferator-activated receptor gamma during ovulation. Gene set enrichment analysis (GSEA) revealed that early stages of oocyte growth involved increases in pathways of natural killer cell and mast cell activation, as well as gap junction regulation. GSEA revealed that arachidonic acid metabolism was significantly up-regulated while CD2, fibronectin, and neuropeptides Y receptor signaling cascades were down-regulated at ovulation. Expression targets for LH signaling were decreased during vitellogenesis but increased at ovulation. GSEA revealed decreases in actin cytoskeleton regulation and receptor mediated signaling pathways involving TGF? and ephrin receptor regulation at atresia. Conclusions: This study offers new insight into the molecular pathways involved in vitellogenesis, ovulation and atresia in LMB and provides new hypotheses about the cellular pathways involved in oocyte growth and maturation. 31 microarrays on 8 unique stages of ovary development; developmental profile time course, development of LMB ovary

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Transcriptional signature of progesterone-induced germinal vesicle breakdown in the fathead minnow ovary (Pimephales promelas)

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