Characterization of the TGF-beta receptor system in bovine granulosa cells

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Infertility in dairy cattle is a principal restraint on economic success in the industry. Abnormal follicle growth and anoestrus is one of the principal causes in declining fertility in high-yielding dairy cattle. To resolve this problem, more basic knowledge is required to understand the endocrine mechanisms that control growth of the ovarian follicle which is the structure that contains the oocyte. Estradiol production by the granulosa cells of the follicle wall is the key to ensure normal follicle development, and estradiol secretion involves complex interactions between circulating molecules and locally produced factors. Transforming growth factor-ß (TGF-ß) is an important factor produced by the follicle cells and is known to modulate estradiol secretion, ovarian function and fertility. In our previous and ongoing studies we have shown that TGF-ß1 is a multifunctional factor which inhibits FSH-stimulated estradiol secretion but stimulates the secretion of estradiol in basal conditions (i.e. in the absence of FSH). The overall objective of my research program is to determine the mechanism of action of TGF-ß on estradiol secretion in bovine granulosa cells. Cultured bovine granulosa cells will be used to characterize the TGF-ß ligand/receptor system. The first objective is to characterize the effects of key hormones (FSH, androstenedione, IGF and insulin) on the mRNA expression of TGF-ß receptors (ALK-5, TGF-ßRII and betaglycan). The second objective is to determine the signal transduction mechanism of TGF-ß receptors looking at 1) the effects of TGF-ß isoforms on the mRNA expression and activation of Smads and 2) the differential effects of TGF-ß1 on gene expression in both basal and FSH-stimulated conditions using bovine gene microarrays. The third objective is to characterize the receptor system of TGF-ß in bovine follicles of different sizes. The study of the TGF-ß receptor/ligand system in bovine follicles as proposed in this research program will provide the basis for future research examining the effects of nutrition and stress on estradiol secretion and follicle development to improve fertility in the bovine species.