Genetic models for transforming growth factor beta superfamily signaling in ovarian follicle development.

The transforming growth factor beta (TGFbeta) superfamily has wide-ranging and profound effects on many aspects of cellular growth and development. Many TGFbeta-related ligands, receptors, and intracellular signaling proteins are expressed in the ovary and are critical for normal follicle development. Our laboratory and others have analyzed the in vivo function of the TGFbeta superfamily signal transduction pathways by using gene knockout and knockin approaches. Two TGFbeta superfamily ligands, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), are expressed in developing oocytes. Based on in vivo data using knockout models, GDF9 is critical at both the primary and preovulatory stages of follicle development, and physiologically interacts with BMP15 during the latter stages of folliculogenesis. A knockin model of activin betaB expressed from the activin betaA locus, revealed that activin betaB can act as a hypomorphic protein and rescue some but not all of activin betaAs functions. Questions of functional redundancy of signaling components and multiple receptor utilization by different ligands still need to be addressed for these pathways. Answers will likely come from using existing single null mouse models to generate combinatorial ligand and receptor null mice. These new models may reveal the in vivo genetic interactions of TGFbeta superfamily ligands, receptors, binding proteins, and downstream signaling pathways.