Targeted disruption of luteinizing hormone β-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility
Targeted disruption of luteinizing hormone β-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility
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DOI：
10.1073/pnas.0404743101
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发表时间：
2004-12-07
影响因子：
11.1
通讯作者：
Kumar, TR
中科院分区：
文献类型：
--
作者：
Ma, XP;Dong, YL;Kumar, TR
黄体生成素（LH）和卵泡刺激素（FSH）作用于性腺细胞，促进甾体生成和配子发生。澄清它们的黄体生成素和卵泡刺激素的作用，为选择性阻断促性腺激素的作用提供了可行的避孕方法。解决这些生理上重要问题的一种方法是产生分离的黄体生成素缺乏的小鼠，并将它们与现有的FSH功能丧失小鼠进行比较。为了模拟包括黄体生成素功能丧失在内的人类生殖障碍，并确定黄体生成素应答基因，我们制造了缺乏激素特异性LHβ亚基的敲除小鼠。lh β-缺失小鼠可以存活，但在出生后表现出性腺生长和功能缺陷，导致不育。突变雄性的睾丸大小减小，间质细胞发育不全，编码类固醇生物合成途径酶的基因表达缺陷，睾丸激素水平降低。此外，精子发生在圆形精子细胞阶段被阻断，导致长形精子细胞完全缺失。突变雌性小鼠性腺功能低下，血清雌二醇和黄体酮水平下降。卵巢组织学显示鞘层正常，卵泡发生缺陷，包括许多退行性窦卵泡，黄体缺失。两性的缺陷不是继发于异常的FSH调节，因为FSH水平在空白小鼠中未受影响。最后，雄性和雌性小鼠均可通过外源性人绒毛膜促性腺激素在药理学上获救，这表明靶细胞的lh反应性并非不可逆转地丧失。因此，LHβ缺失小鼠代表了一种模型，可以研究分离的LH配体缺乏在生殖过程中的后果，同时在靶细胞中保持正常的LH反应性。
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) act on gonadal cells to promote steroidogenesis and gametogenesis. Clarifying thein vivoroles of LH and FSH permits a feasible approach to contraception involving selective blockade of gonadotropin action. One way to address these physiologically important problems is to generate mice with an isolated LH deficiency and compare them with existing FSH loss-of-function mice. To model human reproductive disorders involving loss of LH function and to define LH-responsive genes, we produced knockout mice lacking the hormone-specific LHβ-subunit. LHβ-null mice are viable but demonstrate postnatal defects in gonadal growth and function resulting in infertility. Mutant males have decreased testes size, prominent Leydig cell hypoplasia, defects in expression of genes encoding steroid biosynthesis pathway enzymes, and reduced testosterone levels. Furthermore, spermatogenesis is blocked at the round spermatid stage, causing a total absence of the elongated spermatids. Mutant female mice are hypogonadal and demonstrate decreased levels of serum estradiol and progesterone. Ovarian histology demonstrates normal thecal layer, defects in folliculogenesis including many degenerating antral follicles, and absence of corpora lutea. The defects in both sexes are not secondary to aberrant FSH regulation, because FSH levels were unaffected in null mice. Finally, both male and female null mice can be pharmacologically rescued by exogenous human chorionic gonadotropin, indicating that LH-responsiveness of the target cells is not irreversibly lost. Thus, LHβ null mice represent a model to study the consequences of an isolated deficiency of LH ligand in reproduction, while retaining normal LH-responsiveness in target cells.