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The ovary: basic biology and clinical implications
JoAnne S. Richards, Stephanie A. Pangas
JoAnne S. Richards, Stephanie A. Pangas
Published April 1, 2010
Citation Information: J Clin Invest. 2010;120(4):963-972. https://doi.org/10.1172/JCI41350.
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The ovary: basic biology and clinical implications

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Abstract

The classical view of ovarian follicle development is that it is regulated by the hypothalamic-pituitary-ovarian axis, in which gonadotropin-releasing hormone (GnRH) controls the release of the gonadotropic hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and that ovarian steroids exert both negative and positive regulatory effects on GnRH secretion. More recent studies in mice and humans indicate that many other intra-ovarian signaling cascades affect follicular development and gonadotropin action in a stage- and context-specific manner. As we discuss here, mutant mouse models and clinical evidence indicate that some of the most powerful intra-ovarian regulators of follicular development include the TGF-β/SMAD, WNT/FZD/β-catenin, and RAS/ERK1/2 signaling pathways and the FOXO/FOXL2 transcription factors.

Authors

JoAnne S. Richards, Stephanie A. Pangas

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Figure 2

Signaling pathways controlling ovarian follicle growth in the mouse.

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Signaling pathways controlling ovarian follicle growth in the mouse.
PGC...
PGCs are specified by the BMP pathway, then proliferate and migrate to the indifferent gonad. The BMPs are major determinants of PGC specification and proliferation in the mouse. During the postnatal period, clusters (or nests) of germ cells break down to form primordial follicles, which upon activation become primary follicles. Estradiol (E2) inhibits the breakdown of germ cell clusters to primordial follicles. A number of mice lacking oocyte transcription factors (TFs) (NOBOX, SOHLH1, SOHLH2, and LHX8) show loss of follicles at the primordial follicle–to–primary follicle transition or before primordial follicle formation (FIGLA). Foxo3 is also expressed in oocytes, and deletion of Foxo3 (or the PI3K inhibitor Pten) in oocytes results in premature activation of the primordial follicle pool and oocyte loss. Foxl2 is expressed in somatic granulosa cells, and deletion results in arrest and subsequent death of follicles before the primary follicle stage. FOXL2 also likely functions at late stages in folliculogenesis. NOBOX regulates other TFs (e.g., Pou5f1) and also Gdf9, the product of which is secreted by the oocyte to regulate granulosa cell function, including suppression of Inha. GDF9 and activin signal though SMAD2/-3. Regulation of activin by its inhibitors, such as inhibin or follistatin, is critical after the secondary follicle stage and involves many follicle stages. In vitro experiments implicate FOXO1 and ESR2 as important regulators in granulosa cells of growing follicles. FSH is a key regulator of the antral and preovulatory stage through multiple signaling cascades, and many of the FSH targets at the preovulatory stage are coregulated by activin (Fshr, Cyp19a1) and/or β-catenin (Cyp19a1). See text for discussion and references for each indicated gene pathway.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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