Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene
Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene
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DOI：
10.1210/me.15.1.184
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发表时间：
2001-01-01
影响因子：
--
通讯作者：
Rao, CV
中科院分区：
文献类型：
--
作者：
Lei, ZM;Mishra, S;Rao, CV
LH/hCG受体在胚胎干细胞中被基因靶向破坏，这种破坏导致两性不育。性腺不含受体mRNA或受体蛋白。两种性别的血清LH水平均大幅升高，FSH水平中度升高;雌性雌二醇和孕酮水平降低，但未完全抑制;雄性睾酮水平显著降低，雌二醇水平中度升高。男女的外生殖器和内生殖器都严重发育不全。流产包括阴道口不清、腹部睾丸、小阴茎、性腺和生殖道重量显著下降、窦期以后卵泡生长停滞、曲细精管紊乱、间质细胞数量减少和营养不良以及圆形精子细胞期以后生精停滞。LH/hCG受体基因阻断对卵巢和睾丸FSH受体mRNA水平、卵巢孕激素受体（PR）水平和睾丸雄激素受体（AR）水平无影响。然而，它导致卵巢和睾丸中SMR和雌激素受体α（ER α）mRNA水平的急剧下降以及ER β mRNA水平的增加。雌激素和孕激素替代治疗的女性和睾酮替代男性，以确定是否表型和生化变化的结果，性腺类固醇水平下降或由于LH信号的损失，揭示了一些和部分恢复的完全恢复。尽管如此，这些动物仍然不育。预计LH受体敲除动物将增加我们目前对LH和hCG的性腺和非性腺作用的理解。
LH/hCG receptors were disrupted by gene targeting in embryonic stem cells, The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testosterone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdominal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round spermatid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in testes. However, it caused a dramatic decrease in SMR and estrogen receptor-alpha (ER alpha) mRNA levels and an increase in ER beta mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phenotype and biochemical changes were a consequence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained infertile. It is anticipated that the LH receptor knockout animals will increase our current understanding of gonadal and nongonadal actions of LH and hCG.