Lapatto Risto, Pallais J Carl, Zhang Dongsheng, Chan Yee-Ming, Mahan Amy, Cerrato Felecia, Le Wei Wei, Hoffman Gloria E, Seminara Stephanie B
Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
Endocrinology. 2007 Oct;148(10):4927-36. doi: 10.1210/en.2007-0078. Epub 2007 Jun 26.
The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43-52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.
G蛋白偶联受体Gpr54及其配体促性腺激素抑制激素（源自Kiss1基因产物亲吻素）是性成熟的关键守门者。Gpr54基因敲除小鼠表现为促性腺激素缺乏性性腺功能减退，但直到最近，Kiss1基因敲除小鼠的表型仍不清楚。本报告描述了在相同遗传背景下携带Kiss1或Gpr54靶向缺失的小鼠的生殖表型。Kiss1和Gpr54基因敲除小鼠均可存活但不育，且性成熟异常；大多数雄性小鼠包皮未分离，雌性小鼠阴道开口延迟且无发情周期。与对照组相比，Kiss1和Gpr54基因敲除雄性小鼠的睾丸明显较小。Gpr54基因敲除雌性小鼠的卵巢和子宫比野生型雌性小鼠小。然而，Kiss1基因敲除雌性小鼠表现出两种不同的表型：一半小鼠的性腺重量明显降低，类似于Gpr54基因敲除小鼠，而另一半小鼠则表现为持续性阴道角化，性腺重量与野生型雌性小鼠相当。Kiss1和Gpr54基因敲除的雄性和雌性小鼠的促卵泡激素水平均显著低于对照组。当注射Gpr54激动剂小鼠促性腺激素抑制激素43 - 52时，Gpr54基因敲除小鼠的促性腺激素未能增加，而Kiss1基因敲除小鼠的促性腺激素水平则升高。总之，Kiss1和Gpr54基因敲除小鼠均有与促性腺激素缺乏性性腺功能减退一致的性成熟异常，尽管Kiss1基因敲除小鼠似乎比其受体基因敲除小鼠受影响程度较轻。Kiss1基因敲除雌性小鼠表现出双峰表型变异，一些动物的性腺重量更高、阴道开口更大且有持续性阴道角化。
