Gonadotropin-releasing hormone regulates transcription of the inhibin B co-receptor, TGFBR3L, via early growth response one.

Abstract

Follicle-stimulating hormone (FSH), a product of pituitary gonadotrope cells, regulates gonadal function and fertility. FSH production is stimulated by gonadotropin-releasing hormone (GnRH) and activin-class ligands of the TGFβ family. Inhibin A and B are TGFβ proteins that suppress FSH synthesis by competitively binding activin type II receptors in concert with the co-receptors betaglycan (TGFBR3) and TGFBR3L. Betaglycan mediates the actions of both inhibins and is broadly expressed. In contrast, TGFBR3L is inhibin B-specific and selectively expressed in gonadotropes. This cell-restricted expression is driven, in part, by steroidogenic factor 1 (SF-1, NR5A1), which stimulates Tgfbr3l/TGFBR3L transcription via two conserved promoter elements. Tgfbr3l expression is lost in mice lacking SF-1 in gonadotropes. However, SF-1 alone is unlikely to fully explain gonadotrope-restricted Tgfbr3l/TGFBR3L expression. Here, we report that GnRH induces binding of the transcription factor, early growth response 1 (EGR1), to the murine Tgfbr3l and human TGFBR3L promoters at a conserved cis-element between the two SF-1 binding sites. In homologous LβT2 cells, GnRH stimulation of Tgfbr3l/TGFBR3L promoter-reporters depends on EGR1 binding to this cis-element. In heterologous cells, over-expressed EGR1 independently and synergistically with SF-1 activates Tgfbr3l/TGFBR3L promoter-reporter activities. In vivo, Tgfbr3l mRNA expression is reduced in the pituitaries of: 1) GnRH-deficient mice, 2) wild-type mice treated with a GnRH receptor antagonist, and 3) gonadotrope-specific Egr1 knockout mice. Gonadectomy, which increases GnRH pulse frequency, enhances Tgfbr3l expression in control but not gonadotrope-specific Egr1 knockouts. Collectively, these data indicate that GnRH stimulates Tgfbr3l/TGFBR3L transcription via EGR1, which acts with SF-1 through conserved promoter elements.