Estradiol induces E-cadherin degradation in mouse uterine epithelium during the estrous cycle and early pregnancy

Mouse uterine epithelium is a tissue that undergoes cyclic endocrine-regulated cell dissociation and regeneration. It shows a dramatic cell loss following normal estrus. If pregnancy ensues, cell loss is averted during the first 2.5–3.5 days. However, this is followed by a precipitous loss of basal-lateral cell adhesion and apoptosis in preparation for blastocyst invasion. By comparing epithelia isolated by protease treatment, we show that a reduction of lateral cell adhesion is a primary event in these instances of normal tissue loss. It was readily induced in ovariectomized adult and immature mice by injections of estradiol (E₂), and to some extent also by progesterone (P₄). The reduction of lateral adhesion induced by including ethylene glycol-bis (β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) in the isolation medium mimicked and was additive to the effect of E₂ injection. However, the E₂ effect was different in not being prevented by adding Ca²⁺. The E₂ effect also was mimicked by the action on isolated epithelium of monoclonal antibody against the calcium-dependent cell adhesion molecule, E-cadherin, suggesting that inactivation of E-cadherin was induced by E₂. In detergent extracts of estrous and metestrous epithelium there was an increase in 80-kDa extracellular domain of E-cadherin relative to the intact 120-kDa molecule. The loss of adhesion between 3.5 and 4.5 days of pregnancy was associated with a loss of both intact membrane-associated 120-kDa E-cadherin and cleavage products. Cleavage of 80-kDa E-cadherin was uniquely induced by E₂ in ovariectomized adult and immature mice; P₄ was without effect. The cleavage of E-cadherin correlated with increased basal accumulation of E-cadherin antigen in estrous and E₂-injected mice and a loss of both basal and lateral antigen at 4.5 days of pregnancy. Only the E-cadherin antigen within junctional complexes appeared unaffected. The data are consistent with the hypothesis that the cyclic and pregnancy-dependent disruption of uterine epithelial integrity are promoted by E₂-dependent modification of E-cadherin, including its extracellular cleavage. © 1996 Wiley-Liss, Inc.