The role of Steroidogenic Factor 1 in testicular Leydig cells

Male sexual development and function in mammals is dependent on the products of the testis. The Leydig cells of the testis produce androgens that determine the development of most male secondary characteristics and support sperm production in the adult. Little is known about the factors that regulate Leydig cell differentiation and function. The nuclear hormone receptor SF1 has been implicated in the development of reproductive tissues including the gonad in both mouse and man. Here we aim to study the role of SF1 in Leydig cell differentiation and hormone production in the embryo and adult mouse. As this factor has various roles in the different cell types of the testis, we have devised a strategy to inactivate SF1 specifically within Leydig cells and to identify its tissue specific partner in these cells. These studies will allow us to understand how the cell types of the gonad differentiate and form an organ and how hormone production is regulated in the embryo and adult. In addition, we will uncover molecular pathways that might be implicated in deficiencies of sexual development and reproductive function in humans.

The goal of this project is to establish the role of the orphan nuclear receptor SF1 in the differentiation and function of the Leydig cells of the testis. SF1 has been implicated in the development of reproductive tissues including the gonad. Within the testis, SF1 is expressed in both Sertoli and Leydig cells, however, its role in these different cell types has not been elucidated nor has the basis for its specificity of action been determined. Using transgenic animals with tissue specific regulatory sequences driving an inducible version of Cre recombinase and mice with a conditional SF1 allele we aim to create Leydig cell-specific SF1 deficient mice at different stages of differentiation and in the adult and analyse their phenotype. In this study we will determine whether SF1 controls cell proliferation and survival in this tissue and whether it controls and maintains the transcription of Leydig cell-specific genes, such as those required for hormone production, in the developing and adult mouse. In addition, using a yeast two-hybrid approach we will identify factors that interact with SF1 within developing Leydig cells, with the aim of establishing the mechanisms of specificity of SF1 action within the testis during embryogenesis. These studies will provide insight into the molecular pathways that are important in Leydig cell development and hormone production in mammals that may help determine the basis for deficiencies of sexual development and reproductive function in humans.