Gonadal defects and hormonal alterations in transgenic mice expressing a single chain human chorionic gonadotropin-lutropin receptor complex
Gonadal defects and hormonal alterations in transgenic mice expressing a single chain human chorionic gonadotropin-lutropin receptor complex
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DOI：
10.1677/jme.1.01669
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Narayan, P
中科院分区：
文献类型：
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作者：
Meehan, TP;Harmon, BG;Narayan, P
为了研究过早和慢性配体介导的促黄体生成激素受体（LHR）激活对生殖发育的影响，我们已经产生了转基因小鼠表达基因工程，组成性活性的轭式受体复合物（YHR），其中人绒毛膜促性腺激素（hCG）的融合蛋白共价连接到大鼠LHR的N-末端。在青春期前和青春期后年龄对表达YHR的小鼠（YHR+）进行了分析。相对于野生型（WT）对照组，雄性小鼠显示青春期前睾酮水平和精囊重量增加，血清FSH、血清LH、睾丸重量和曲细精管大小减少。在成年雄性YHR+小鼠中，睾酮和LH水平与WT对照组无显著差异。然而，FSH水平和睾丸重量仍然下降。雌性YHR+小鼠经历性早熟，阴道提前开放、子宫发育加速、卵泡发育增强（包括黄体的存在）和血清孕酮增加。在12周龄时，卵巢表现出间质组织数量的相对增加，包括肥大和黄素化的细胞以及退化的卵泡。此外，大约25%的转基因小鼠会出现出血性囊肿。这些退行性变化与卵巢老化一致，表明CG诱导的雌性小鼠LHR激活导致性早熟发育和卵巢病变。总之，这些数据表明，单链YHR在体内是功能性的，并证明YHR+小鼠提供了一种新的系统，以进一步了解异常LHR激活的生殖后果。
To study the effects of premature and chronic ligand-mediated luteinizing hormone receptor (LHR) activation on reproductive development, we have generated transgenic mice expressing a genetically engineered, constitutively active yoked hormone-receptor complex (YHR), in which a fusion protein of human chorionic gonadotropin (hCG) is covalently linked to the N-terminus of rat LHR. YHR-expressing mice (YHR+) were analyzed at pre- and post-pubertal ages. Relative to wild type (WT) controls, male mice exhibited prepubertal increases in testosterone levels and seminal vesicle weights, and decreases in serum FSH, serum LH, testes weight, and the size of the seminiferous tubules. In adult male YHR+ mice, testosterone and LH levels are not significantly different from WT controls. However, FSH levels and testes weights remain decreased. Female YHR+ mice undergo precocious puberty with early vaginal opening, accelerated uterine development, enhanced follicular development, including the presence of corpora lutea, and an increase in serum progesterone. At 12 weeks of age, the ovary exhibits a relative increase in the amount of interstitial tissue, comprised of cells that are hypertrophic and luteinized, as well as follicles that are degenerating. Additionally, hemorrhagic cysts develop in approximately 25% of the transgenic mice. These degenerative changes are consistent with an aging ovary suggesting that CG-induced LHR activation in female mice leads to precocious sexual development and ovarian lesions. Taken together, these data indicate that the single chain YHR is functional in vivo and demonstrate that YHR+ mice provide a novel system to further understand the reproductive consequences of aberrant LHR activation.