ALTERATION OF REPRODUCTIVE FUNCTION BUT NOT PRENATAL SEXUAL DEVELOPMENT AFTER INSERTIONAL DISRUPTION OF THE MOUSE ESTROGEN-RECEPTOR GENE
ALTERATION OF REPRODUCTIVE FUNCTION BUT NOT PRENATAL SEXUAL DEVELOPMENT AFTER INSERTIONAL DISRUPTION OF THE MOUSE ESTROGEN-RECEPTOR GENE
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DOI：
10.1073/pnas.90.23.11162
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发表时间：
1993-12-01
影响因子：
11.1
通讯作者：
SMITHIES, O
中科院分区：
文献类型：
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作者：
LUBAHN, DB;MOYER, JS;SMITHIES, O
长期以来，雌激素受体及其配体雌二醇一直被认为是生存、生育和女性性别分化和发育所必需的。与这一被提出的关键作用一致，目前还没有发现人类雌激素受体基因突变，这与雄激素受体不同，在雄激素受体中发现了许多功能缺失的突变。我们已经通过基因打靶扰乱雌激素受体基因，产生了对雌二醇缺乏反应性的突变小鼠。雄性和雌性动物都能存活到成年，大体外部表型正常。女性不育；男性生育力下降。女性子宫发育不全，卵巢充血，未发现黄体。在成年野生型和杂合子雌性动物中，以40毫克/公斤的剂量进行为期3天的雌二醇治疗可以刺激子宫湿重增加3到4倍，并改变阴道角化，但在雌激素受体基因缺失的动物中，子宫和阴道没有反应。因此，在没有雌激素受体介导的反应性的情况下，胎儿期男性和女性生殖道的发育可能会发生。
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 mug/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.