Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene
Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene
复制标题
DOI：
10.1073/pnas.0704114104
复制
发表时间：
2007-06-19
影响因子：
11.1
通讯作者：
Colledge, William H.
中科院分区：
文献类型：
--
作者：
d'Anglemont de Tassigny, Xavier;Fagg, Lisa A.;Colledge, William H.
G蛋白偶联受体GPR 54（AXOR 12，OT 7 T175）是哺乳动物获得生殖能力的核心。该受体的肽配体（kisspeptins）由Kiss 1基因编码，外源性kisspeptins的给药可刺激包括人类在内的几个物种的下丘脑促性腺激素释放激素（GnRH）释放。为了确定kisspeptins是体内GPR 54的真正激动剂，并确定这些配体是否具有额外的生理功能，我们已经产生了Kiss 1基因靶向破坏的小鼠。Kiss 1基因敲除的小鼠是存活的，健康的，没有明显的异常，但不能经历性成熟。突变的雌性小鼠不通过发情周期，具有线状子宫和小卵巢，并且不产生成熟的Graffian卵泡。突变的雄性有小睾丸，精子发生主要在早期的单倍体精子细胞停止。阶段两性都有低循环促性腺激素（促黄体激素和促卵泡激素）和性类固醇（β-雌二醇或睾酮）激素水平。GnRH神经元迁移到下丘脑似乎是正常的，与正中隆起和总GnRH含量有适当的轴突连接。在这些小鼠中，下丘脑-垂体轴是功能性的，如通过在外周施用kisspeptin后稳健的促黄体激素分泌所示。Gpr 54-和Kiss 1-null小鼠几乎相同的表型提供了直接证据，证明kisspeptins是体内GPR 54受体的真正生理配体。Kiss 1似乎也没有发挥重要作用，在任何其他生理过程以外的下丘脑-垂体-性腺轴的激活，和Kiss 1的损失不能克服的补偿机制。
The G protein-coupled receptor GPR54 (AXOR12, OT7T175) is central to acquisition of reproductive competency in mammals. Peptide ligands (kisspeptins) for this receptor are encoded by the Kiss1 gene, and administration of exogenous kisspeptins stimulates hypothalamic gonadotropin-releasing hormone (GnRH) release in several species, including humans. To establish that kisspeptins are the authentic agonists of GPR54 in vivo and to determine whether these ligands have additional physiological functions we have generated mice with a targeted disruption of the Kiss1 gene. Kiss1-null mice are viable and healthy with no apparent abnormalities but fail to undergo sexual maturation. Mutant female mice do not progress through the estrous cycle, have thread-like uteri and small ovaries, and do not produce mature Graffian follicles. Mutant males have small testes, and spermatogenesis arrests mainly at the early haploid spermatic! stage. Both sexes have low circulating gonadotropin (luteinizing hormone and follicle-stimulating hormone) and sex steroid (beta-estradiol or testosterone) hormone levels. Migration of GnRH neurons into the hypothalamus appears normal with appropriate axonal connections to the median eminence and total GnRH content. The hypothalamic-pituitary axis is functional in these mice as shown by robust luteinizing hormone secretion after peripheral administration of kisspeptin. The virtually identical phenotype of Gpr54- and Kiss1-null mice provides direct proof that kisspeptins are the true physiological ligand for the GPR54 receptor in vivo. Kiss1 also does not seem to play a vital role in any other physiological processes other than activation of the hypothalamic-pituitary-gonadal axis, and loss of Kiss1 cannot be overcome by compensatory mechanisms.