Sertoli and granulosa cells form an important somatic component of the gonads. These cells help regulate germ cell development by providing essential nutrients and regulatory signals that support their maturation. In turn, Sertoli and granulosa cells are influenced by a host of cellular associations and intricate sets of endocrine and paracrine signals. The complexities of this system serve to underscore the need to develop animal models to study how Sertoli and granulosa cell factors impact gonadal function. Such studies will ultimately improve approaches for birth control and for treating gonadal abnormalities and infertility. SF-1 and CREB emerge as proteins critical for Sertoli and granulosa cell function. These proteins, like many others, have been characterized within these cells but their role in mediating germ cell development remains obscure. This proposal tests the importance of these proteins, while developing a new transgenic approach that will specifically over- express proteins in Sertoli and granulosa cells. This work will not only provide valuable animal models to elucidate gonadal functions of SF-1 and CREB but will yield important technology that is advantageous to many, as it provides a means to create animal models that express elevated levels of proteins while using a weak but highly specific promoter. Four lines of transgenic mice will be created. Two will contain transgenes in which the Cre recombinase gene is expressed from the follicle-stimulating hormone receptor promoter. This promoter is active only in Sertoli and granulosa cells of the gonads and therefore Cre recombinase will reside only in these cells of transgenic mice. Two other lines f mice will contain targeting transgenes designed to over- express either SF-1 or a dominant negative form of CREB from a strong ubiquitous promoter. The genes for these proteins will not be active unless a recombination event occurs which is facilitated by Cre recombinase when Cre expressing mice are mated with mice harboring the targeting transgenes. Recombination and therefore over-expression of SF-1 and CREB will occur only in Sertoli and granulosa cells of doubly transgenic mice.
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