Paracrine role of MIS in Steroidogenesis

MIS is a glycoprotein in the TGFbeta family of Growth and differentiation factors whose role in fetal Mullerian regression is critical to normal male sexual development. The Sertoli cells begin producing MIS in humans at 7 weeks gestation as a result of the earlier SRY initiated testicular maturational steps. MIS production continues into adulthood in both sexes, which may underlie its role as a regulator of adult gonadal function. Adult transgenic mice over expressing MIS develop severe gonadal abnormalities including Leydig cell hypoplasia, lowered testosterone levels, and subfertility. Mice that are null for MIS or the type II receptor develop the opposite phenotype, showing Leydig cell hyperplasia and elevated testosterone levels. Previous experiments by this lab have shown that MIS inhibits testosterone production at the transcriptional level and may also do this by inhibition of the lyase step. To better delineate the mechanism's of the lyase suppression I plan to investigate MIS's effect using a viral-promoter driven P450c17 gene, and I also plan to examine MIS's effect on the phosphorylation state of the P450c17 enzyme, a potential regulatory of lyase activity. Finally I will perform gene array experiments using recombinant human MIS and MA-10 cells. The results of this effort will allow me to begin to study the molecular pathways involved in MIS signaling and androgen synthesis.