Monday, August 2, 2004
10:30 AM–12:30 PM
(139) A 'DEFAULT' TESTIS? EXISTENCE OF AN Sry-INDEPENDENT PATHWAY IN MAMMALIAN TESTIS DETERMINATION.
Yao, Humphrey 1, Aardema, Jorie1, Brown, Alicia2, Holthusen, Kirsten 1, Joseph, Avenel1, 1 Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois2 Department of Animal Sciences, University of Illinois, Urbana, Illinois
ABSTRACT- Mammalian testis development is a dominant event initiated by Sry (Sex-determining Region of the Y chromosome). In contrast, ovary development is considered as a default process, arising only in the absence of Sry. We recently identified a novel pathway consisting of Wnt4 and follistatin (Fst) in ovary development. The Wnt4/Fst pathway antagonizes certain aspects of testis development in the ovary. In Wnt4 or Fst null ovaries, a testis-specific coelomic vessel emerged. We also discovered that Fst acts downstream of Wnt4 to inhibit coelomic vessel formation. In this study, we investigated how Wn4/Fst pathway inhibits testis vasculature in the ovary. Fst is known as an inhibitor of activins. We found that activin beta B (AcbB), but not Activin beta A, was expressed in both embryonic testis and ovary, albeit a much lower level in the ovary. We therefore hypothesize that the Wnt4/Fst pathway inhibits AcbB, which is responsible for coelomic vessel formation in the absence of Wnt4 or Fst. Indeed, AcbB expression was significantly elevated in Wnt4 null ovaries. Furthermore, exogenous AcbB induced coelomic vessel formation in ovaries in culture. Because coelomic vessel formation is normally an event downstream of Sry and Sertoli cell differentiation, we investigated whether Sertoli cell differentiation was activated in Wnt4 null ovary. Sox9, the master gene downstream of Sry for Sertoli cell differentiation, was not expressed in Wnt4 or Fst null ovary. This indicates that expression of AcbB and formation of the coelomic vessel do not require Sertoli cell differentiation, nor does it require Sry, as this gene is not present in females. Based on these findings, we propose that the Wnt4/Fst pathway inhibits AcbB expression and its ability to induce coelomic vessel in embryonic ovary. AcbB and the consequent formation of testis-specific coelomic vessel are a default process independent of Sry and Sertoli cell differentiation. To provide genetic evidence to support this hypothesis, we are examining whether inactivation of AcbB in either Wnt4 or Fst null ovaries can rescue the coelomic vessel phenotype. Moreover, we expect that inactivation of AcbB in embryonic testis will affect normal development of the coelomic vessel. Our results will provide a novel perspective challenging the existing paradigm in mammalian sex determination.
KEY WORDS: activin, Wnt4, sex determination, follistatin