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-r egulated cell dissociation and regeneration. It shows a dramatic cell loss following normal estrus. If pregnancy ensues, cell loss is averte d during the first 2.5-3.5 days. However, this is followed by a precip itous 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 prim ary event in these instances of normal tissue loss. It was readily ind uced in ovariectomized adult and immature mice by injections of estrad iol (E(2)), and to some extent also by progesterone (P-4). The reducti on of lateral adhesion induced by including ethylene glycol-bis (beta- aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) in the isolation m edium mimicked and was additive to the effect of E(2) injection. Howev er, the E(2) effect was different in not being prevented by adding Ca2 +. The E(2) effect also was mimicked by the action on isolated epithel ium of monoclonal antibody against the calcium-dependent cell adhesion molecule, E-cadherin, suggesting that inactivation of E-cadherin was induced by E(2). In detergent extracts of estrous and metestrous epith elium there was an increase in 80-kDa extracellular domain of E-cadher in relative to the intact 120-kDa molecule. The loss of adhesion betwe en 3.5 and 4.5 days of pregnancy was associated with a loss of both in tact membrane-associated 120-kDa E-cadherin and cleavage products. Cle avage of 80-kDa E-cadherin was uniquely induced by E(2) in ovariectomi zed adult and immature mice; P-4 was without effect. The cleavage of E -cadherin correlated with increased basal accumulation of E-cadherin a ntigen in estrous and E(2)-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 consiste nt with the hypothesis that the cyclic and pregnancy-dependent disrupt ion of uterine epithelial integrity are promoted by E(2)-dependent mod ification of E-cadherin, including its extracellular cleavage. (C) 199 6 Wiley-Liss, Inc.