UTERINE AND VAGINAL ORGAN GROWTH REQUIRES EPIDERMAL GROWTH-FACTOR RECEPTOR SIGNALING FROM STROMA

Estrogens are crucial for growth and function of the female genital tr act. Recently, we showed that induction of uterine epithelial prolifer ation by estradiol is a paracrine event requiring an estrogen receptor -positive stroma. Growth factors [such as EGF (epidermal growth factor ) ligands] are likely paracrine mediators, which may directly or indir ectly regulate epithelial proliferation in estrogen target organs via cell-cell interactions. In this report, we used mice with a null mutat ion in their EGF receptor (EGFR) to examine the role of EGFR signaling in growth of the uterus and vagina and in estrogen-induced uterine an d vaginal epithelial proliferation. When WT and EGFR-knockout (EGFR-KO ) uteri and vaginae were grown as renal capsule grafts in nude mice, g rowth of uterine and vaginal grafts of EGFR-KO mice was reduced, compa red with their WT counterparts. Grafts of both EGFR-KO uteri and vagin ae were about one third smaller (wet weight) than their corresponding WT organs, even though differentiation of both epithelium and mesenchy me were normal in both cases. Both wild-type and EGFR-KO vaginal graft s contained within their lumina alternating layers of cornified and mu cified epithelial cell layers, indicating cyclic alteration of epithel ial differentiation. In response to estradiol treatment, stromal cell labeling index (LI), as assessed by incorporation of H-3-thymidine, wa s severely depressed in EGFR-KO uterine and vaginal grafts vs. stromal cell LI in WT uterine and vaginal grafts. Unexpectedly, epithelium of both EGFR-KO and wild-type grafts responded comparably to estradiol w ith a marked elevation (similar to 7-fold overall) of epithelial LI in response to estradiol in uterine and vaginal epithelia. These data su pported the hypothesis that overall uterine and vaginal organ growth, in response to estrogen, required EGFR signaling for DNA synthesis in the fibromuscular stroma, whereas EGFR signaling was not essential for estrogen-induced epithelial growth in the uterus and vagina.