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Linkage of regulators of TGF-? activity in the fetal ovary to polycystic ovary syndrome.

ABSTRACT: Although not often discussed, the ovaries of women with polycystic ovary syndrome (PCOS) show all the hallmarks of increased TGF-? activity, with increased amounts of fibrous tissue and collagen in the ovarian capsule or tunica albuginea and ovarian stroma. Recent studies suggest that PCOS could have fetal origins. Genetic studies of PCOS have also found linkage with a microsatellite located in intron 55 of the extracellular matrix protein fibrillin 3. Fibrillins regulate TGF-? bioactivity in tissues by binding latent TGF-? binding proteins. We therefore examined expression of fibrillins 1-3, latent TGF-? binding proteins 1-4, and TGF-? 1-3 in bovine and human fetal ovaries at different stages of gestation and in adult ovaries. We also immunolocalized fibrillins 1 and 3. The results indicate that TGF-? pathways operate during ovarian fetal development, but most important, we show fibrillin 3 is present in the stromal compartments of fetal ovaries and is highly expressed at a critical stage early in developing human and bovine fetal ovaries when stroma is expanding and follicles are forming. These changes in expression of fibrillin 3 in the fetal ovary could lead to a predisposition to develop PCOS in later life.

SUBMITTER: Hatzirodos N

PROVIDER: S-EPMC3219214 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Linkage of regulators of TGF-β activity in the fetal ovary to polycystic ovary syndrome.

Hatzirodos Nicholas N Bayne Rosemary A RA Irving-Rodgers Helen F HF Hummitzsch Katja K Sabatier Laetitia L Lee Sam S Bonner Wendy W Gibson Mark A MA Rainey William E WE Carr Bruce R BR Mason Helen D HD Reinhardt Dieter P DP Anderson Richard A RA Rodgers Raymond J RJ

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20110316 7

Although not often discussed, the ovaries of women with polycystic ovary syndrome (PCOS) show all the hallmarks of increased TGF-β activity, with increased amounts of fibrous tissue and collagen in the ovarian capsule or tunica albuginea and ovarian stroma. Recent studies suggest that PCOS could have fetal origins. Genetic studies of PCOS have also found linkage with a microsatellite located in intron 55 of the extracellular matrix protein fibrillin 3. Fibrillins regulate TGF-β bioactivity in ti ...[more]

PMID: 21411746

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Project description:Polycystic Ovary Syndrome (PCOS) is a multifactorial syndrome with reproductive, endocrine, and metabolic symptoms, affecting about 10% women of reproductive age. Pathogenesis of the syndrome is poorly understood with genetic and fetal origins being the focus of the conundrum. Genetic predisposition of PCOS has been confirmed by candidate gene studies and Genome-Wide Association Studies (GWAS). Recently, the expression of PCOS candidate genes across gestation has been studied in human and bovine fetal ovaries. The current study sought to identify potential upstream regulators and mechanisms associated with PCOS candidate genes. Using RNA sequencing data of bovine fetal ovaries (62-276 days, n = 19), expression of PCOS candidate genes across gestation was analysed using Partek Flow. A supervised heatmap of the expression data of all 24,889 genes across gestation was generated. Most of the PCOS genes fell into one of four clusters according to their expression patterns. Some genes correlated negatively (early genes; C8H9orf3, TOX3, FBN3, GATA4, HMGA2, and DENND1A) and others positively (late genes; FDFT1, LHCGR, AMH, FSHR, ZBTB16, and PLGRKT) with gestational age. Pathways associated with PCOS candidate genes and genes co-expressed with them were determined using Ingenuity pathway analysis (IPA) software as well as DAVID Bioinformatics Resources for KEGG pathway analysis and Gene Ontology databases. Genes expressed in the early cluster were mainly involved in mitochondrial function and oxidative phosphorylation and their upstream regulators included PTEN, ESRRG/A and MYC. Genes in the late cluster were involved in stromal expansion, cholesterol biosynthesis and steroidogenesis and their upstream regulators included TGFB1/2/3, TNF, ERBB2/3, VEGF, INSIG1, POR, and IL25. These findings provide insight into ovarian development of relevance to the origins of PCOS, and suggest that multiple aetiological pathways might exist for the development of PCOS.

Dataset Information

Linkage of regulators of TGF-? activity in the fetal ovary to polycystic ovary syndrome.

Publications

Linkage of regulators of TGF-β activity in the fetal ovary to polycystic ovary syndrome.

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