ALTERATION OF REPRODUCTIVE FUNCTION BUT NOT PRENATAL SEXUAL DEVELOPMENT AFTER INSERTIONAL DISRUPTION OF THE MOUSE ESTROGEN-RECEPTOR GENE

Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiati on and development. Consistent with this proposed crucial role, no hum an estrogen receptor gene mutations are known, unlike the androgen rec eptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disruptin g the estrogen receptor gene by gene targeting. Both male and female a nimals survive to adulthood with normal gross external phenotypes. Fem ales are infertile; males have a decreased fertility. Females have hyp oplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatmen t at 40 mug/kg stimulates a 3- to 4-fold increase in uterine wet weigh t and alters vaginal cornification, but the uteri and vagina do not re spond in the animals with the estrogen receptor gene disruption. Prena tal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.