Studies Towards Understanding the Functional Significance of Multiple GnRHs in Vertebrate Brains

PI：Zohar，Y.IBN-9723643促性腺激素释放激素(GnRH‘s)是在大脑中产生的十肽，对所有脊椎动物的生殖都是不可或缺的。这些神经激素通过调节脑下垂体促性腺激素的合成和释放来发挥作用。然而，在所有脊椎动物中，多种形式的促性腺激素释放激素在单个物种的大脑中共存，这表明在进化过程中，促性腺激素释放激素可能获得了与生殖无关的额外功能。多个GnRH的不同作用尚不完全清楚，它们在生殖过程中的相对参与也尚未确定。到目前为止，在脊椎动物中已经描述了九种不同形式的促性腺激素释放激素，其中六种是鱼类特有的。虽然现在认为在所有脊椎动物的大脑中都存在两到三种形式的促性腺激素释放激素，但波斯鱼是第一种，也是迄今为止唯一一种在单一物种的大脑中确定了三种形式的脊椎动物。这三种GnRH形式已经在多肽和核苷酸水平上得到了完全的表征。因此，Perciform鱼是目前研究脊椎动物GnRH多重性与生殖相关意义的最佳模型。这项研究的主要目的是了解多种促性腺激素释放激素的哪种形式参与生殖控制，并阐明这些形式与生殖相关的相对作用。PI将使用条纹鱼和金枪鱼作为实验模型，这两种鲤鱼都具有三种GnRH形式。这些鱼的生殖内分泌学已经得到了广泛的研究，拟议研究所需的所有生化和遗传工具都很容易获得。将检验三个假设：1)参与生殖调节的GnRH的基因表达和肽水平在性腺发育的不同阶段不同；2)参与生殖的那些形式的基因表达和肽水平对影响配子发生的环境变化做出反应；以及3)与生殖相关的GnRH的基因表达和肽水平受性腺类固醇反馈的调节。这些研究结果将有助于全球理解GnRH多样性在包括哺乳动物在内的所有脊椎动物中的功能意义。这项研究也有望为今后在器官、细胞和分子水平上调节与生殖相关的GnRH形式的生物合成和释放奠定基础。最后，由于养殖鱼类的生殖障碍似乎是由于GnRH干扰所致，这项研究的结果可能对商业鱼类养殖具有重大影响。

PI: Zohar, Y. IBN-9723643 Gonadotropin releasing hormones (GnRH's) are decapeptides produced in the brain that are integral for reproduction in all vertebrates. These neurohormones function by regulating gonadotropin synthesis and release in the pituitary. The discovery, however, that in all vertebrates, multiple forms of GnRH coexist in the brain of a single species, indicates that during evolution GnRH's may have acquired additional functions that are not related to reproduction. The differential roles of the multiple GnRH's are not yet fully understood, and their relative involvement in reproduction has yet to be defined. Nine distinct forms of GnRH have been described thus far in vertebrates, out of which six are fish-specific. Although two to three forms of GnRH are now believed to be present in the brains of all vertebrates, perciform fish were the first, and to date, the only vertebrates in which three forms have been definitively identified in the brain of a single species. These three GnRH forms have been completely characterized both at the peptide and nucleotide level. Therefore, at present, perciform fish represent the best available model for studying the reproduction-related significance of GnRH multiplicity in vertebrates. The primary objective of the proposed research is to understand which of the multiple forms of GnRH are involved in the control of reproduction, and to elucidate the relative reproduction-related roles of these forms. The PI will use striped bass and gilthead seabream, both perciform fish possessing three GnRH forms as experimental models. The reproductive endocrinology of these fish has been studied extensively, and all biochemical and genetic tools required for the proposed studies are readily available. Three hypotheses will be tested: 1) That gene expression and peptide levels of those GnRH's that are involved in the regulation of reproduction vary at different stages of gonadal development; 2) That the gene expression an peptide levels of those forms that are involved in reproduction are responsive to environmental changes that influence gametogenesis; and, 3) That gene expression and peptide levels of reproductively-relevant GnRH's are regulated by gonadal steroid feedback. The results of these studies will contribute to the global understanding of the functional significance of GnRH multiplicity in all vertebrates including mammals. It is also expected that this research will pave the way for future studies concerned with the regulation of biosynthesis and release of GnRH forms relevant to reproduction , at the organisimal, cellular and molecular levels. Finally, as reproductive failure in farmed fish appears to be due to GnRH disruption, the results of this research may have significant implications for commercial fish farming.