Progesterone and heparin-binding epidermal growth factor-like growth factor regulate the expression of tight junction protein Claudin-3 during early pregnancy.

ABSTRACT

OBJECTIVE: To determine Claudin-3 expression and its regulatory factors during embryo implantation. DESIGN: Experimental mouse models and cell culture. SETTING: University research laboratory. ANIMAL(S) Sexually mature female CD-1 strain mice. INTERVENTION(S) Ovariectomy and treatments. MAIN OUTCOME MEASURE(S) In situ hybridization and immunohistochemistry for detecting Claudin-3 messenger RNA and protein expression in mouse uterus, respectively; Western blot for detecting protein levels; immunofluorescence for detecting Claudin-3 protein in cultured cells. RESULT(S) Claudin-3 is strongly expressed in the uterine luminal epithelium on days 3 and 4 of pregnancy, and diminished at day 5 implantation sites. Then it is expressed at secondary decidual zone on day 8. Pseudopregnant uteri have a similar expression pattern as pregnant uteri from days 1-5. Claudin-3 expression is down-regulated after delayed implantation is activated by estrogen (E) treatment. Meanwhile Claudin-3 expression is stimulated by artificial decidualization. In ovariectomized mice, P induces Claudin-3 expression in the luminal epithelium, which is abrogated by P receptor antagonist RU486. Heparin-binding-epidermal growth factor (HB-EGF) down-regulates Claudin-3 expression, but enhances transcription factor Snail expression. In human endometrial epithelial ECC-1 cells, both E and P could stimulate Claudin-3 expression, whereas HB-EGF decreases Claudin-3 and increases Snail expression. CONCLUSION(S) Claudin-3 expression in uterine luminal epithelium is stimulated by P and suppressed by HB-EGF in mice and humans.