Estrogen receptor transcription and transactivation: Estrogen receptor knockout mice - what their phenotypes reveal about mechanisms of estrogen action

Estrogen has many roles in reproduction, and the generation of the estrogen receptor (ER)α and ERβ knockout (αERKO and βERKO) mice has further illustrated its roles and mechanisms. Interestingly, both sexes of the αERKO mice are infertile, whereas only the βERKO female has shown impaired fertility. In the male αERKO mice, infertility is due to deficits at several points in the reproductive process, including severe reduction in sperm numbers and lack of sperm function, as well as abnormal sexual behavior. The seminiferous tubules of the αERKO testes show progressive dilation that is accompanied by degeneration of the seminiferous epithelium (Fig. 1) [1*,2*]. Transplanted αERKO sperm was functional when developed in normal host testes [3**]. In contrast, the testes of the βERKO mice appear normal (Fig. 1), and produce sufficient and functional sperm to allow fertility, resulting in production of offspring in mice examined to date. Therefore, ERα appears to be more critical than ERβ in mediation of the estrogen actions necessary for maintenance of healthy testicular structures and the somatic cell function required for successful sperm maturation.Normally, the female rodent reproductive tract grows and matures in response to cycling ovarian hormones, including estradiol. The growth and maturation of the epithelial portion and the preparation of the stromal layer is thought to be important for successful implantation and pregnancy to occur. The infertility of the female αERKO mouse is due in part to the insensitivity of the uterus to the mitogenic and differentiative actions of estrogen [4**,5**] (Fig. 2). Microscopic evaluation of the αERKO uterine tissue indicates that all expected tissues are present but appear immature, as illustrated by a reduced number of glands in the endometrium (Fig. 3). ERα is thus not necessary for development of the uterus, but is necessary for complete maturation and function of the tissue. In contrast, the wild-type and βERKO uteri are in