Studies of Polycystic Ovary Syndrome Candidate Genes and the Developing Fetal Ovary
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Date
2021
Authors
Liu, Menghe
Editors
Advisors
Hummitzsch, Katja
Irving-Rodgers, Helen
Irving-Rodgers, Helen
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Thesis
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Abstract
The cause of polycystic ovary syndrome (PCOS) is not well understood and hence there are no syndrome-specific treatments nor prevention strategies. PCOS appears to have both genetic and fetal origins. The polycystic ovary is fibrous with expanded amounts of stroma and it is not known why and if this represents a fibrosis later in life or merely altered stroma formation and growth during fetal ovary development. The work in this thesis attempts to link these facts to begin to understand the aetiology of PCOS. Previously our group had identified the origin and examined the growth of ovarian stroma in the fetal ovary. They had also identified a second somatic cell type, the gonadal ridge epithelial-like (GREL) cells that are likely progenitors of granulosa cells and surface epithelial cells. No one had previously isolated these GREL cells and cultured them. A procedure for purifying bovine GREL cells and fetal ovarian fibroblasts was established. The optimised procedure includes culture of fetal ovarian cells on collagen type I-coated surfaces in the presence of EGF and clonal expansion of pure GREL cell or fibroblast clones. The cells exhibited different morphologies. We examined gene expression in these cells and in their adult cell counterparts that include adult ovary fibroblasts, granulosa cells and surface epithelial cells. We discovered that the GREL cells differ in expression of a number of genes to fetal fibroblasts and that both cells are also different to their adult counterparts. Thus, clearly the fetal somatic cells are of two lineages. We examined the expression of PCOS candidate genes that were in loci identified previously by GWAS and microsatellite mapping. We looked in control and PCOS ovaries from adults and across gestation in bovine and human fetal ovaries. By far the most exciting data were in the fetal ovaries with genes expressed either early, late or continuously across gestation. In the former two groups the expression levels of genes were highly correlated with each other. However, there were very few differences in expression between GREL cells and fetal ovarian stromal cells. Finally, we cultured fetal fibroblasts with a range of growth factors. Importantly, TGFβ1 regulated a number of the PCOS candidate genes inhibiting the expression of 7 of the 25 PCOS candidate genes as well as of AR, and stimulating expression of the AR co-activator TGFB1I1. TGFβ is a master regulator of stromal fibroblasts stimulating in the adult collagen deposition, cell replication and fibrosis. In summary, these studies provide further understanding of the cells involved in fetal ovarian development and the development of a predisposition to PCOS. Importantly, they suggest that alterations in TGFβ signalling during fetal ovary development are a likely candidate to be involved in the aetiology of PCOS.
School/Discipline
Adelaide Medical School
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2022
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This thesis is currently under Embargo and not available.