Activation of luteinizing hormone β gene by gonadotropin-releasing hormone requires the synergy of early growth response-1 and steroidogenic factor-1

We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) beta deficiency. Egr-1 activates the LH beta gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function, To test if this synergy is essential for gonadotropin-releasing hormone (GnRH) stimulation of LH beta, we examined the activity of the LH beta promoter in the gonadotrope cell line L beta T2. GnRH markedly stimulated the LH beta promoter (15-fold). Mutation of either Egr-1 or SF-1 elements within the LH beta promoter attenuated this stimulation, whereas mutation of both promoter elements abrogated GnRH induction of the LH beta promoter. Furthermore, GnRH stimulated Egr-1 but not SF-1 expression in L beta T2 cells. Importantly, overexpression of Egr-1 alone was sufficient to enhance LH beta expression. Although other Egr proteins are expressed in L beta T2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust, We also found that the nuclear receptor DAX-1, a repressor of SF-1 activity, reduced Egr-1-SF-1 synergy and diminished GnRH stimulation of the LH beta promoter. We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LH beta gene and plays a central role in the dynamic regulation of LH beta expression.