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A new model of development of the mammalian ovary and follicles.

Hummitzsch K, Irving-Rodgers HF, Hatzirodos N, Bonner W, Sabatier L, Reinhardt DP, Sado Y, Ninomiya Y, Wilhelm D, Rodgers RJ.

PLoS One. 2013;8(2):e55578.

Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, SA, Australia.



Ovarian follicular granulosa cells surround and nurture oocytes, and produce sex steroid hormones. It is believed that during development theovarian surface epithelial cells penetrate into the ovary and develop into granulosa cells when associating with oogonia to form follicles. Using bovine fetal ovaries (n = 80) we identified a novel cell type, termed GREL for Gonadal Ridge Epithelial-Like. Using 26 markers for GREL and other cells and extracellular matrix we conducted immunohistochemistry and electron microscopy and chronologically tracked all somatic cell types during development. Before 70 days of gestation the gonadal ridge/ovarian primordium is formed by proliferation of GREL cells at the surface epithelium of the mesonephros. Primordial germ cells (PGCs) migrate into the ovarian primordium. After 70 days, stroma from the underlying mesonephros begins to penetrate the primordium, partitioning the developing ovary into irregularly-shaped ovigerous cords composed of GREL cells and PGCs/oogonia. Importantly we identified that the cords are always separated from the stroma by a basal lamina. Around 130 days of gestation the stroma expands laterally below the outermost layers of GREL cells forming a sub-epithelial basal lamina and establishing an epithelial-stromal interface. It is at this stage that a mature surface epithelium develops from the GREL cells on the surface of the ovary primordium. Expansion of the stroma continues to partition the ovigerous cords into smaller groups of cells eventually forming follicles containing an oogonium/oocyte surrounded by GREL cells, which become granulosa cells, all enclosed by a basal lamina. Thus in contrast to the prevailing theory, the ovarian surface epithelial cells do not penetrate into the ovary to form the granulosa cells offollicles, instead ovarian surface epithelial cells and granulosa cells have a common precursor, the GREL cell.


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A number of major important health conditions in women involve ovaries.  Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder of women of reproductive age at around 5%.  Women suffer infertility, symptoms of excess androgens and are predisposed to becoming obese and developing type 2 diabetes and dyslipidaemia.  Recent evidence from our research (FASEB Journal 2011, 25, 2256-2265) suggests that the predisposition to PCOS in adult life can originate when the fetal ovary develops.  Specifically we found that the gene linked to PCOS, fibrillin 3, is expressed in the ovarian stroma as the ovary develops (FASEB Journal 2011, 25, 2256-2265).  As our studies of fetal ovaries continued (PLOS ONE 2013, 8(2):e55578) it became clear to us that the current and earlier hypotheses on how the ovary develops were not correct.  The model we propose is very simple and has implication for the study of PCOS as we now know where and how the stroma of the ovary develops.


Our study also has value for understanding premature ovarian failure.  Premature ovarian failure occurs in about 1% of women and about 70% of cases are of unknown causes.  One hypothesis suggests that the number of follicles formed during development of the fetal ovary could be inadequate, leading to premature depletion of the follicle reserve and hence premature menopause.  Our study identifies how follicles are formed, where the somatic cells of the follicle come from and also importantly the roles of stroma in this process (PLOS ONE 2013, 8(2):e55578).  Knowing these things will no doubt enable researchers to identify processes that could be compromised leading to a reduced follicle reserve.


Our study also has implications for ovarian cancers.  The majority of cancers are of an epithelial nature and a recent study suggests that the majority of cancer prone cells are located at the base or hilum of the ovary (Flesken-Nikitin et al. 2013, Nature doi:10.1038/nature11979).  From our studies it is clear that the base or hilum of the ovary has an epithelial layer that is derived directly from the mesonephros, whereas the remainder of the ovary has surface epithelial cells derived from gonadal-ridge epithelial like cells (PLOS ONE 2013, 8(2):e55578).  This observation could explain why the epithelial cells at the base of the ovary behave differently to those, elsewhere on the surface of the ovary.