UC San Diego

In the anterior pituitary, activin is a potent inducer of the FSHb gene. The gene is a critical subunit that regulates the synthesis of FSH and thus regulates reproduction. Smad3 is a transcription factor that conveys activin responsiveness, and we have identified a novel region of the FSHb promoter as a major site of Smad3 action. In this region, we have identified a protein of the Forkhead (Fox) family of transcription factors that binds to a site. The activity for the FoxL2 transcription factor is located at -350 from the transcriptional start site. This site is critical for induction by activin, Smad3 and activin receptor, ALK7. FoxL2 is a novel player in pituitary gene expression that has been shown to interact with Smad3 and play a role in ovary development and therefore reproduction. Furthermore, we identified other FoxL2 binding sites at -200 and -153 that bind FoxL2 with varying affinity. These sites also play a role in activin and Smad3 induction. In the porcine promoter, the -153 site is a high affinity binding site for FoxL2, while in the human promoter, the -200 site confers higher affinity binding. Nevertheless, both sites confer a role in activin induction. Therefore, FoxL2 is a critical player for activin regulation of the FSHb gene in multiple species, although the affinity of the sites may vary.