Intraovarian activins are required for female fertility

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 beta A 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 beta A were intercrossed to Inhbb homozygous null mice to produce double activin knockouts. Whereas ovarian beta A knockout females are subfertile, beta B/beta A double mutant females are infertile. Strikingly, the activin beta A and beta B/beta A- 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 beta A and beta B function redundantly in a growth stimulatory pathway in the mammalian ovary.