Hom Y K, Young P, Wiesen J F, Miettinen P J, Derynck R, Werb Z, Cunha G R
Department of Anatomy, University of California, San Francisco 94143, USA.
Endocrinology. 1998 Mar;139(3):913-21. doi: 10.1210/endo.139.3.5817.
Estrogens are crucial for growth and function of the female genital tract. Recently, we showed that induction of uterine epithelial proliferation 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 indirectly regulate epithelial proliferation in estrogen target organs via cell-cell interactions. In this report, we used mice with a null mutation in their EGF receptor (EGFR) to examine the role of EGFR signaling in growth of the uterus and vagina and in estrogen-induced uterine and vaginal epithelial proliferation. When WT and EGFR-knockout (EGFR-KO) uteri and vaginae were grown as renal capsule grafts in nude mice, growth of uterine and vaginal grafts of EGFR-KO mice was reduced, compared with their WT counterparts. Grafts of both EGFR-KO uteri and vaginae were about one third smaller (wet weight) than their corresponding WT organs, even though differentiation of both epithelium and mesenchyme were normal in both cases. Both wild-type and EGFR-KO vaginal grafts contained within their lumina alternating layers of cornified and mucified epithelial cell layers, indicating cyclic alteration of epithelial differentiation. In response to estradiol treatment, stromal cell labeling index (LI), as assessed by incorporation of 3H-thymidine, was 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 with a marked elevation (approximately 7-fold overall) of epithelial LI in response to estradiol in uterine and vaginal epithelia. These data supported 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.
雌激素对于女性生殖道的生长和功能至关重要。最近，我们发现雌二醇诱导的子宫上皮增殖是一个旁分泌事件，需要雌激素受体阳性的基质。生长因子[如表皮生长因子（EGF）配体]可能是旁分泌介质，它们可通过细胞间相互作用直接或间接调节雌激素靶器官中的上皮增殖。在本报告中，我们使用表皮生长因子受体（EGFR）基因敲除的小鼠来研究EGFR信号通路在子宫和阴道生长以及雌激素诱导的子宫和阴道上皮增殖中的作用。当野生型（WT）和EGFR基因敲除（EGFR-KO）的子宫和阴道作为肾包膜移植在裸鼠体内生长时，与野生型对照相比，EGFR-KO小鼠的子宫和阴道移植组织的生长受到抑制。尽管两种情况下上皮和间充质的分化均正常，但EGFR-KO小鼠的子宫和阴道移植组织（湿重）比相应的野生型器官小约三分之一。野生型和EGFR-KO阴道移植组织的腔内均含有角化和黏液化上皮细胞层的交替层，表明上皮分化呈周期性变化。通过掺入3H-胸腺嘧啶评估，与野生型子宫和阴道移植组织中的基质细胞标记指数（LI）相比，EGFR-KO子宫和阴道移植组织中对雌二醇治疗的基质细胞LI严重降低。出乎意料的是，EGFR-KO和野生型移植组织的上皮对雌二醇的反应相当，子宫和阴道上皮中雌二醇诱导的上皮LI显著升高（总体约7倍）。这些数据支持了以下假设：雌激素作用下子宫和阴道器官的整体生长需要EGFR信号通路参与纤维肌性基质中的DNA合成，而EGFR信号通路对于雌激素诱导的子宫和阴道上皮生长并非必不可少。
