Transforming growth factor β family signaling pathways in ovarian and uterine biology

PROJECT SUMMARY Transforming growth factor β (TGFβ) family signaling pathways function in normal physiology and diverse reproductive tract diseases including infertility, preeclampsia, and endometriosis. There are 33 TGFβ family ligands, and these proteins act as either homodimers [e.g., bone morphogenetic proteins (BMPs), activins, and nodal] or heterodimers (e.g., inhibins and GDF9:BMP15). These dimeric ligands signal from the cell surface to the nucleus by assembling heteromeric serine-threonine kinase receptor complexes that include two type 1 receptors [known as activin-like kinases (ALKs)] and two type 2 receptors. With 33 years of support from NICHD, we have defined the in vivo roles of TGFβ family ligands, receptors, binding proteins, SMADs, and downstream proteins in the female and male reproductive tracts, created over 300 mouse models for studying human fertility, published over 170 papers to genetically and chemically interrogate these signaling pathways in development, physiology, infertility, and cancer, and have begun to generate the first specific kinase inhibitors of the TGFβ family receptors. In particular, whereas mammalian oocytes were initially thought to be merely passengers rather than drivers in ovarian development, we discovered that growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are essential oocyte-secreted TGFβ family ligands in the regulation of female fertility in mammals that bind a unique receptor signaling complex. We hypothesize that specific small-molecule regulators of GDF9:BMP15, activin, BMP, and nodal signaling can be used to manipulate fertility pathways and modulate ovarian and uterine functions in vitro and in vivo. The overall translational goals of this R01 renewal are to use mouse models, ALK-specific small molecules, and recombinant protein strategies to genetically manipulate, chemically modulate, and structurally characterize GDF9:BMP15, activin, BMP, and nodal signaling pathways in the mammalian ovary and uterus. Our 5-year studies will create an assortment of drug-like molecules that can either block or stimulate TGFβ family signaling pathways, thereby serving as non-hormonal contraceptives or as treatments for infertility, preeclampsia, and endometriosis in the clinic.