Activins have diverse roles in multiple physiological processes including reproduction. Mutations and loss of heterozygosity at the human
activin receptor ACVR1B and ACVR2 loci are observed in pituitary, pancreatic, and
colorectal cancers. Functional studies support intraovarian roles for
activins, although clarifying the in vivo roles has remained elusive due to the
perinatal death of
activin betaA knockout mice. To study the roles of
activins in ovarian growth, differentiation, and
cancer, a tissue-specific knockout system was designed to ablate ovarian production of
activins. Mice lacking ovarian
activin betaA were intercrossed to Inhbb homozygous null mice to produce double
activin knockouts. Whereas ovarian betaA knockout females are subfertile, betaB/betaA double mutant females are infertile. Strikingly, the
activin betaA and betaB/betaA-deficient ovaries contain increased numbers of functional corpora lutea but do not develop ovarian
tumors. Microarray analysis of isolated granulosa cells identifies significant changes in expression for a number of genes with known reproductive roles, including Kitl, Taf4b, and Ghr, as well as loss of expression of the proto-oncogene, Myc. Thus, in contrast to the known
tumor suppressor role of
activins in some tissues, our data indicate that
activin betaA and betaB function redundantly in a growth stimulatory pathway in the mammalian ovary.