Regulation of sialomucin complex/Muc4 expression in rat uterine luminal epithelial cells by transforming growth factor-?: Implications for blastocyst implantation

Abstract

Blastocyst implantation is arguably the most critical stage of mammalian embryogenesis and requires that the uterus be in a receptive state. Initiation of receptivity involves loss of anti-adhesive molecules from the apical surface of the uterine luminal epithelium, one of which is sialomucin complex (SMC/Muc4), a highly O-glycosylated, anti-adhesive glycoprotein composed of mucin ascites sialoglycoprotein-1 (ASGP-1) and transmembrane (ASGP-2) subunits. SMC expression at the uterine luminal surface, but not in glandular epithelium, is hormonally regulated and varies with the estrous cycle. SMC is lost from the luminal uterine surface at the period of receptivity. However, the mechanism by which SMC is hormonally regulated is not understood. Analyses of SMC regulation in hormone-responsive primary cultures of rat uterine luminal epithelial cells (RULEC) demonstrated robust SMC expression by the RULEC, which is not altered by treatments with estrogen or progesterone. However, both SMC protein and transcript are downregulated by transforming growth factor-beta (TGF-beta1). SMC is also downregulated when RULEC are co-cultured with isolated uterine stromal cells. Estradiol and anti-TGF-beta block the stromal cell effect. These results suggest an indirect hormonal regulation of RULEC SMC, in which TGF-beta acts as a hormonally regulated, mesenchymal paracrine factor to repress SMC production by the epithelial cells and permit implantation.