Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice
Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice
复制标题
DOI：
10.1073/pnas.1321404111
复制
发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
Kumar, T. Rajendra
中科院分区：
文献类型：
--
作者：
Wang, Huizhen;Larson, Melissa;Kumar, T. Rajendra
FSH 和黄体生成素 (LH) 分别由许多脊椎动物的垂体促性腺激素组成型或脉冲式分泌，并调节卵巢功能。这种进化上保守的促性腺激素特异性分泌模式的分子基础尚不清楚。在这里，我们证明 LH 中的羧基端七肽是体内促性腺激素分选决定因素，可指导脉冲式分泌。含有这种七肽的 FSH 进入转基因小鼠促性腺激素的调节途径，并响应促性腺激素释放激素而释放，类似于 LH。从 LH 分泌途径释放的 FSH 可以像组成型分泌的 FSH 一样有效地挽救 Fshb 缺失小鼠的卵巢缺陷。有趣的是，改变后的 FSH 增强了卵泡的存活率，导致排卵次数急剧增加，并延长了女性的生殖寿命。此外，改变路线的FSH极大地提高了卵子的体内受精能力、随后的体外发育以及移植后产生后代的能力。我们的研究证明了通过改变垂体营养激素的细胞内运输和分泌命运来微调靶组织反应的可行性。这种在体内相互转换蛋白质分泌命运的方法具有病理生理学意义，并且可以解释几种激素过度刺激和抵抗综合征的病因。
FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.