DEVELOPMENTAL & FUNCTIONAL ROLES OF ACTIVIN & INHIBIN

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Activin and inhibin are members of a large family of dimeric growth factors which also includes Mullerian inhibiting substance (MIS), and several transforming growth factor beta's (TGF-beta's)(1-16). Activin is a homodimeric beta:beta protein and inhibin is a heterodimeric alpha:beta protein with the beta subunit (either betaA or betaB activin) common to the two proteins (1-3). Both activin and inhibin, similar to the other growth factors in this family, have been postulated to be important in a number of differentiation and developmental events (1-3, 20-22, 25, 26). The goal of this project is to understand the developmental and physiological roles of inhibin and activin. These studies will address whether activin is physiologically important as a mesoderm inducing factor in mammals, whether each of the activin beta subunits have different developmental roles, especially in brain development, and whether activin and inhibin play important paracrine, autocrine, and endocrine functions in pituitary and gonadal development. In phase I of this project, the aims are: 1) Clone and characterize the mouse alpha inhibin, betaA activin, and betaB activin genes; 2) Construct vectors from these mouse genes for use in homologous recombination experiments and generation of embryonic stem cell lines with mutations at these loci; 3) Produce mice which are homozygous and heterozygous for these mutant alleles; and 4) Analyze the morphologic, histologic, and biochemical consequences of mutations at the a inhibin, betaA activin and betaB activin loci to address the roles of activin and inhibin in the above-mentioned developmental processes. Phase II of this project involves: 1) Further morphologic, histologic, and biochemical characterization of the mutant mice produced in phase I; and 2) Crossbreeding of mice carrying these different mutant alleles in their germlines to produce mice deficient in several of the activins and inhibins.