AN ESSENTIAL ROLE FOR C EBP-BETA IN FEMALE REPRODUCTION/

A large number of intercellular signaling molecules have been identifi ed that orchestrate female reproductive physiology. However, with the exception of steroid hormone receptors, little information exists abou t the transcriptional regulators that mediate cellular responses to th ese signals. The transcription factor C/EBP beta (CCAAT/enhancer-bindi ng protein beta) is expressed in ovaries and testes, as well as many o ther tissues of adult mice. Here we show that mice carrying a targeted deletion of the C/EBP beta gene exhibit reproductive defects. Althoug h these animals develop normally and males are fertile, adult females are sterile. Transplantation of normal ovaries into mutant females res tored fertility, thus localizing the primary reproductive defect to th e ovary proper. In normal ovaries, C/EBP beta mRNA is specifically ind uced by luteinizing hormone (LH/hCG) in the granulosa layer of preovul atory antral follicles. C/EBP beta-deficient ovaries lack corpora lute a and fail to down-regulate expression of the prostaglandin endoperoxi dase synthase 2 and P450 aromatase genes in response to gonadotropins. These findings demonstrate that C/EBP beta is essential for periovula tory granulosa cell differentiation in response to LH. C/EBP beta is t hus established as a critical downstream target of G-protein-coupled L H receptor signaling and one of the first transcription factors, other than steroid hormone receptors, known to be required for ovarian foll icle development in vivo.