CELL-SPECIFIC EXPRESSION OF ACTIVIN AND ITS 2 BINDING-PROTEINS IN THE RAT DECIDUA - ROLE OF ALPHA(2)-MACROGLOBULIN AND FOLLISTATIN

Rat decidual tissue is formed by two distinct decidual cell populations located either antimesometrially or mesometrially in the uterus. They differ in morphology, the genes they express, the proteins they secrete, and the role they play during pregnancy. Recently, we have shown that rat decidua expresses follistatin and alpha(2)-macroglobulin (alpha(2)-MG), two binding proteins to activin. In the present study, we determined whether the decidua of pregnant and pseudopregnant rats also expresses activin, whether activin messenger RNA (mRNA) is confined to a particular cell population, and whether it is regulated by its binding proteins. Decidual and placental tissues were collected at different stages of pseudopregnancy or pregnancy. mRNA expression was examined by in situ hybridization, reverse transcription-polymerase chain reaction, and Northern analysis. Developmental studies revealed that activin A became highly expressed in the antimesometrial decidua only from day 11 at a time when this tissue was undergoing extensive degeneration. Very little activin A mRNA could be detected in the mesometrial decidua. However, late in pregnancy, significant expression of activin A mRNA was detected in the mesometrial decidua undergoing extensive cell death at this stage. Developmental study revealed that activin A mRNA became expressed in the antimesometrial decidua only when follistatin mRNA disappeared from this tissue. Furthermore, mesometrial decidua expressing the most alpha(2)-MG mRNA had reduced levels of activin A mRNA. These data suggest that follistatin and alpha(2)-MG may, by binding to activin, prevent activin A from stimulating the expression of its own gene. To examine this possibility we first established that the rat decidua expresses activin receptor II at a constant level between days 11-15. Then we examined whether follistatin and alpha(2)-MG down-regulate activin expression in a simian virus 40-transformed decidual cell line (GG-AD). These cells express activin A mRNA in abundance, very little follistatin, and no alpha(2)-MG. Follistatin and alpha(2)-MG caused a dose-related decrease in activin A mRNA levels in these cells. The same inhibitory effect was observed with activin A-blocking antibody. In summary, the results of this investigation demonstrate that rat decidual tissue expresses mRNAs for activin A and its two binding proteins; follistatin and alpha(2)-MG. The expression of each mRNA is cell specific and developmentally regulated. The finding that both activin-binding proteins and antibody inhibit the expression of activin A in cultured decidual cells suggests that activin regulates its own gene expression in the decidua. The sequential expression of follistatin first and then activin A in the antimesometrial cells together with the low expression of activin A mRNA in mesometrial cells that express high level alpha(2)-MG mRNA strongly suggest that these two decidua-derived activin-binding proteins direct the expression pattern and the level of activin A mRNA in the two decidual cell populations during development. High expression of activin A in the decidual cell population undergoing apoptosis suggests a physiological role in the decidual tissue regression and reorganization necessary for fetal development.