PARENT SESSION
MINISYMPOSIUM III. TGFβ SUPERFAMILY SIGNALING IN REPRODUCTION

Monday, August 2, 2004
9:00 AM–10:30 AM
Buchanan A104
Chair: Alan Schneyer (Massachusetts General Hospital-Harvard Medical School, Boston, MA)

(MS8) THE TGF SUPERFAMILY IN SPERMATOGENESIS: FUNCTIONAL ANALYSES OF ACTIVIN AND BAMBI.

Loveland, Kate^{1, 2}, Bakker, Marilyn¹, Mendis, Sirisha¹, Brown, Chester³, Meachem, Sarah⁴, Escalona, Ruth ⁴, Ooi, Guck⁴, ¹ Monash University, Melbourne, Victoria, Australia² The Australian Research Council Centre of Excellence in Biotechnology and Development, Melbourne, Australia³ Baylor College of Medicine, Houston, Texas⁴ Prince Henry's Institute for Medical Research, Melbourne, Victoria, Australia

ABSTRACT- Several TGF superfamily members affect specific stages of spermatogenesis. In particular, activin A, BMP-4 and GDNF modulate stem cell development and spermatogonial differentiation at the onset of spermatogenesis in the newborn rodent. We reported previously that activin A mRNA and protein disappear from quiescent rat gonocytes as they differentiate into spermatogonia, and this occurs as the activin antagonists, follistatin and Bambi (BMP and activin membrane-bound inhibitor), appear. In the mouse, this period is followed by elevated production of BMP4 by Sertoli cells, and BMP4 and activin appear to promote germ cell differentiation. To investigate how differing bioactive activin levels affect early spermatogenesis, we are using the A knockout and B knock-in (BK) mouse models. The A-/- mice die at birth, and the onset of fertility is delayed in BK/BK males. While Sertoli cell proliferation appears impaired in newborn A-/- mice, the BK/BK mice show a reduction in both germ cell and Sertoli cell proliferation at 2 weeks postpartum. These data indicate that lower levels of bioactive activin affect Sertoli cells and germ cells at different stages of testicular development. We also investigated the role of Bambi in spermatogenesis. While it was reported to act as a dominant-negative signaling inhibitor at the plasma membrane, we have observed the protein both on the cell surface and at intracellular sites during differentiation of the male germ cell. In functional studies with reporter constructs in cell lines, the influence of Bambi on TGF superfamily signaling appears to vary between cell lines and species of origin. We observed agonist and null functional impacts in addition to the predicted antagonistic function with in vitro signal transduction assays. Our current hypothesis is that this molecule should be renamed: Bamboozled, and we are working to more fully characterize its roles in cell signaling and spermatogenesis.

KEY WORDS: bambi, transforming growth factor superfamily, activin, spermatogenesis