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Regulatory roles of transforming growth factor beta family members in folliculogenesis

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Abstract Bidirectional signaling between the oocyte and surrounding somatic cells is absolutely essential for successful germ cell development in mammals. Oocytes secrete proteins that are necessary for granulosa cells growth and differentiation, whilst granulosa cells regulate oocyte development and integrate ovarian function with the rest of the body by orchestrating gonadal steroidogenesis. The importance of communication between the oocyte and granulosa cells is highlighted by genetic deletion of members of the transforming growth factor beta (TGFβ) family and their downstream signaling components. Such knockout models have uncovered an interesting spectrum of reproductive phenotypes that have greatly advanced our knowledge of ovarian function and dysfunction. The current review focuses on some of the more recent transgenic mouse models that elucidate the intraovarian TGFβ signaling vital for oocyte and granulosa cell development. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Developmental Biology > Lineages

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(a) A simple schematic representation of the canonical transforming growth factor beta (TGFβ) signal transduction system. TGFβ family ligands bind type II and type I receptors to activate and stabilize the complex. The type I receptor then phosphorylates the receptor‐activated SMAD proteins (R‐SMAD), which then form trimers with the common SMAD4 (C‐SMAD). This active SMAD complex can then translocate into the nucleus to regulate target genes. (b) Activin, TGFβ, and bone morphogenetic protein (BMP) induce different receptor complexes and receptor‐activated SMAD signaling cascades. The promiscuity and the combination of receptor and signal transduction proteins are evident in Table 1, although new insights into receptor and SMAD combinations are continually discovered.

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Periodic‐acid Schiff's (PAS)‐hematoxylin stained sections showing the ovarian phenotypes of adult control mice (a) and the conditional ablations of Smad1 and Smad5 (b), Smad4 (c) and Smad2 and Smad3 (d) signaling proteins. (a) A low power image of an adult control (wild type) mouse ovary shows follicles of various developmental stages. Small primordial and primary (arrow) follicles are located around the ovarian cortex. Primordial follicles are too small to be seen at this magnification. Primary follicles develop into secondary follicles (SFs), which then progress to antral follicle (AnF) stage with appropriate hormonal stimulation. An oocyte (Oo) surrounded by layers of granulosa cells (Gr) is indicated in the antral follicle. After ovulation, the oocyte is released and the resulting granulosa cells are left to form the corpus luteum (CL). The oviduct (Ovi) is located adjacent to the ovary. Mice with granulosa cell‐specific ablation of SMAD proteins demonstrate severe disruptions in folliculogenesis and defects in ovulation. (b) An adult Smad1 Smad5 dcKO ovary exhibits very few follicles and regressing corpora lutea (CL). These mice develop granulosa cell tumors, shown here spreading outside of the ovary (arrow) into the bursal space, fat pad, and Oviduct. (c) High magnification image of a Smad4 cKO during ovulation. Smad4 cKO mice do not develop tumors, but exhibit severe reproductive abnormalities. This includes disorganized expansion of cumulus cells (Cu) and detachment of the cells from the oocyte in both small (*) and large antral follicles. (d) Low power image of a Smad2 Smad3 dcKO ovary. The Smad2 Smad3 dcKO has similar reproductive defects to Smad4. With the exception of a few scattered follicles, the ovary is devoid of healthy antral follicles and CLs, and follicular atresia is evident by the remaining extracellular matrix of the oocyte (zona pellucida remnants) (arrowheads). Images are not to scale.

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Crosstalk between the oocyte and granulosa cells (both cumulus and mural) is integral for various stages of folliculogenesis. Oocyte‐derived bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) act via SMAD 1/5/8 and 2/3 respectively, to elicit cellular responses that are essential for successful folliculogenesis and ovulation.

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