Alteration of Reproductive Function but Not Prenatal Sexual Development After Insertional Disruption of the Mouse Estrogen Receptor Gene

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-12, Vol.90 (23), p.11162-11166
• Main Authors: Lubahn, Dennis B., Moyer, Jeffrey S., Golding, Thomas S., Couse, John F., Korach, Kenneth S., Smithies, Oliver
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; DNA Primers - chemistry; Embryology: invertebrates and vertebrates. Teratology; Estrogen receptors; Estrogens; Estrogens - metabolism; Exons; Experimental organogenesis; Female; Female animals; Fertility; Fertility - physiology; Fundamental and applied biological sciences. Psychology; Genes; Genetic mutation; Genetics; Male; Male animals; Male fertility; Mice; Mice, Knockout; Molecular Sequence Data; Organogenesis. Physiological fonctions; Ovary - embryology; Phenotype; Polymerase chain reaction; Receptors, Estrogen - physiology; Reproduction; Reproductive system; Restriction Mapping; Rodents; Sex Differentiation - physiology; Sexual development; Uterus; Uterus - embryology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.23.11162

Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 μg/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.