Kauffman Alexander S, Gottsch Michelle L, Roa Juan, Byquist Alisa C, Crown Angelena, Clifton Don K, Hoffman Gloria E, Steiner Robert A, Tena-Sempere Manuel
Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, Washington 98195-7290, USA.
Endocrinology. 2007 Apr;148(4):1774-83. doi: 10.1210/en.2006-1540. Epub 2007 Jan 4.
The Kiss1 gene codes for kisspeptins, which have been implicated in the neuroendocrine regulation of reproduction. In the brain, Kiss1 mRNA-expressing neurons are located in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. Kiss1 neurons in the AVPV appear to play a role in generating the preovulatory GnRH/LH surge, which occurs only in females and is organized perinatally by gonadal steroids. Because Kiss1 is involved in the sexually dimorphic GnRH/LH surge, we hypothesized that Kiss1 expression is sexually differentiated, with females having more Kiss1 neurons than either males or neonatally androgenized females. To test this, male and female rats were neonatally treated with androgen or vehicle; then, as adults, they were left intact or gonadectomized and implanted with capsules containing sex steroids or nothing. Kiss1 mRNA levels in the AVPV and ARC were determined by in situ hybridization. Normal females expressed significantly more Kiss1 mRNA in the AVPV than normal males, even under identical adult hormonal conditions. This Kiss1 sex difference was organized perinatally, as demonstrated by the observation that neonatally androgenized females displayed a male-like pattern of adulthood Kiss1 expression in the AVPV. In contrast, there was neither a sex difference nor an influence of neonatal treatment on Kiss1 expression in the ARC. Using double-labeling techniques, we determined that the sexually differentiated Kiss1 neurons in the AVPV are distinct from the sexually differentiated population of tyrosine hydroxylase (dopaminergic) neurons in this region. Our findings suggest that sex differences in kisspeptin signaling from the AVPV subserve the cellular mechanisms controlling the sexually differentiated GnRH/LH surge.
Kiss1基因编码 Kisspeptin 蛋白，该蛋白与生殖的神经内分泌调节有关。在大脑中，表达 Kiss1 mRNA 的神经元位于弓状核（ARC）和室周前腹侧核（AVPV）。AVPV 中的 Kiss1 神经元似乎在产生排卵前促性腺激素释放激素（GnRH）/促黄体生成素（LH）高峰中发挥作用，这种高峰仅在雌性中出现，并且在围产期由性腺类固醇组织形成。由于 Kiss1 参与了具有性别差异的 GnRH/LH 高峰，我们推测 Kiss1 的表达存在性别差异，雌性比雄性或新生期雄激素化的雌性具有更多的 Kiss1 神经元。为了验证这一点，对雄性和雌性大鼠在新生期用雄激素或赋形剂进行处理；然后，成年后，使其保持完整或进行性腺切除，并植入含有性类固醇或不含任何物质的胶囊。通过原位杂交测定 AVPV 和 ARC 中的 Kiss1 mRNA 水平。即使在相同的成年激素条件下，正常雌性在 AVPV 中表达的 Kiss1 mRNA 也明显多于正常雄性。这种 Kiss1 的性别差异是在围产期形成的，这一观察结果表明，新生期雄激素化的雌性在成年期 AVPV 中呈现出类似雄性的 Kiss1 表达模式。相比之下，ARC 中 Kiss1 的表达既没有性别差异，也不受新生期处理的影响。使用双标记技术，我们确定 AVPV 中具有性别差异的 Kiss1 神经元与该区域中具有性别差异的酪氨酸羟化酶（多巴胺能）神经元群体不同。我们的研究结果表明，AVPV 中 Kisspeptin 信号传导的性别差异有助于控制具有性别差异的 GnRH/LH 高峰的细胞机制。
