NIH R01 HD044464-06: Regulation of Reproductive Function by Activin
The most recognized action of activin is to stimulate follistatin-stimulating hormone (FSH) production by the pituitary gonadotrope in vitro and in vivo. Our work in the past five years has led to a consolidated model of activin-controlled pituitary FSH regulation and an expansion of our understanding regarding the species-specified role of activin in the gonadtropin surge spacing. We were also the first group to solve the structure of activin together with its binding receptor (ActRIIB) and a major bioneutralizing protein, follistatin (FST). While these are major advancements in our understanding of activin signaling, there are still fundamental gaps in our knowledge about the independent roles of activin A and B and the duration and modification of their respective signaling cascades. Our preliminary data show that activin B engages the type I receptors ALK4 and ALK7, while activin A is restricted to ALK4. This receptor distinction results in Smad2, Smad3, and Smad1 phosphorylation downstream of activin B, while activin A signals are confined to Smads 2 and 3. Moreover, FST binds activin B with lower affinity than activin A. Taken together, our data suggest that both the cell signaling and extracellular bioneutralization of these two ligands differs. These differences are important because activin B and not activin A controls pituitary FSH biosynthesis. Finally, new work from our lab reveals differential degradation pathways of the Smads, revealing a new level of cellular control over gene networks in tissue targets. The central hypothesis that we will now test is that multi-component receptor complexes are assembled differentially based on unique structural features of the two activin isoforms and that signaling duration is regulated by receptor internalization, FST binding and clearance, and intracellular Smad activation and processing. By addressing this hypothesis and its tenets, we will provide further insight into the control of pituitary FSH release and follicle formation and in so doing contribute to our understanding of one of most important peptide hormones in reproductive.