Impaired steroid hormone production has been linked to poor reproductive health and congenital anomalies; therefore, proper differentiation of steroidogenic lineages is of paramount importance. Although structurally and functionally distinct, the major steroid-producing organs, the gonads and adrenal cortex, arise from a common pool of progenitors in the urogenital ridge. Despite extensive investigation, the factors that determine whether a steroidogenic cell precursor adopts a gonadal or adrenocortical phenotype are not understood. In the proposed studies, we will utilize novel mouse models of altered cell fate determination to examine the molecular basis of normal and pathological steroidogenic cell development. We will focus on transcription factor GATA-4, a key arbiter of steroidogenic cell fate. In mice, GATA-4 is expressed in sex steroid-producing cells of the gonad, but not in corticoid-producing cells of the adult adrenal. Changes in the expression of GATA-4 appear to influence the phenotype of steroidogenic cells. In preliminary experiments, we have found that targeted mutagenesis of Gata4 is associated with a defect in the differentiation of sex steroidogenic lineages; conversely, ectopic expression of this transcription factor can transform adrenocortical cells into tissue resembling gonadal stroma. We hypothesize that GATA-4, working in concert with gonadotropins and other hormones, determines the functional identity of steroidogenic cells.
Three specific aims will be pursued.
Aim 1 will examine the impact of GATA-4 deficiency on the differentiation of sex steroidogenic cells in ES cell-derived teratomas and embryoid bodies.
In Aim 2, we will assess the role of GATA-4 in sex steroidogenesis using chimeric mice.
In Aim 3, we will determine the effect of forced expression of GATA-4 on differentiation of adrenocortical cells in transgenic mice. These studies should shed light on the molecular basis of normal and pathological steroidogenic cell development. ? ? ?
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