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Evolution of corticosteroid receptor signalling pathways in vertebrates

脊椎动物皮质类固醇受体信号通路的进化

基本信息

批准号：
BB/E001637/1
负责人：
Nicolas Bury
金额：
$ 35.17万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE001637%2F1
关键词：
Evolution corticosteroid receptor signalling pathways

项目摘要

Steroid hormone receptors are proteins mediating the actions of steroid hormones. Similar to a lock and its key, any given receptor binds only one, or few similar, hormones. The binding of a steroid to its receptor induces the transport of the receptor-hormone complex into the cellular nucleus. Here, the complex binds to specific sequences of target genes, the expression of which is in turn modulated. Hence, steroid receptors can be seen as cellular switches through which steroid hormones turn gene expression on or off. Specific receptors exist for the sexual steroids, which include oestrogens, androgens and progestins, and for the steroids synthesised by the adrenal cortex, also called corticosteroids, which include cortisol and aldosterone. The present project focuses on the evolution of corticosteroid receptors. In mammals including man, two corticosteroid receptors (CRs) exist: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Cortisol acts through the GR and has important roles in the regulation of general metabolism, stress response and immune function. By contrast, aldosterone has an important role in the maintenance of the hydromineral balance, and these effects are mediated through the MR. Teleost fish (bony fish, the most diverse and evolutionary most recent group of fishes), lack aldosterone. By contrast, cortisol plays an important role in hydromineral regulation of teleosts and is traditionally considered their main and most important corticosteroid hormone. Recently, however, an MR was discovered in teleosts. This finding resurrected the question whether teleost fish could possibly possess a specific mineralocorticoid hormone. In the present project, we chose an evolutionary approach to better our understanding of corticosteroid signalling in vertebrates. Using molecular biology, we would like to determine the gene sequences for CRs in two relic fish that diverged at crucial points in vertebrate evolution, the lamprey and the bichir. This will enable us to study the properties and tissue distribution of these hormone receptors, which will allow first conclusions about the possible roles of the CRs in these animals. The lamprey, a jawless fish that has diverged from the line leading to the jawed vertebrates 500 MYA, has only one CR, the sequence of which is known partially, and can synthesise cortisol, but not aldosterone. An analysis of the sequence of the lamprey CR indicated that the common ancestor of lampreys and jawed vertebrates had only one CR. Studying the lamprey CR will allow us to gain insights into the properties and functions of the ancestral CR. In the lineage leading to the jawed vertebrates, the ancestral CR gene was duplicated to give rise to the ancestral GR and MR. In sarcopterygians (a systematic group that includes mammals) these two genes were retained, but adopted different roles (see above). Moreover, the enzymes needed for the biosynthesis of aldosterone must have evolved. In the actinopterygians (ray-finned fish), the sister group of sarcopterygians, the ancestral GR and MR were also retained, as they are still present in teleosts, a derived subgroup of actinopterygians. Teleost fish, however, are in evolutionary terms peculiar because in their ancestry a whole genome-duplication occurred, meaning that a given mammalian gene potentially can have two teleost counterparts. While teleosts appear later to have lost many of the duplicated genes, they retained two GRs. We will study the CRs in the bichir, because it represents a basal actinopterygian, having diverged before the teleost-specific genome duplication. We therefore expect that the bichir has, as sarcopterygians, one GR and one MR. Our question is in how far the properties and tissue distribution of the bichir CRs resemble those in the few studied teleosts. Because of the particular evolutionary history of bichir, similarities between bichir and the studied teleosts should apply to the majority of teleosts.

类固醇激素受体是介导类固醇激素作用的蛋白质。就像锁和钥匙一样，任何给定的受体都只能结合一种或几种类似的激素。类固醇与其受体的结合诱导受体-激素复合物转运到细胞核中。在这里，复合物与靶基因的特定序列结合，靶基因的表达反过来被调节。因此，类固醇受体可以被视为细胞开关，类固醇激素通过它打开或关闭基因表达。性类固醇（包括雌激素、雄激素和孕激素）和肾上腺皮质合成的类固醇（也称为皮质类固醇，包括皮质醇和醛固酮）存在特异性受体。本项目的重点是皮质类固醇受体的演变。在包括人在内的哺乳动物中，存在两种皮质类固醇受体（CR）：糖皮质激素受体（GR）和盐皮质激素受体（MR）。皮质醇通过GR发挥作用，在一般代谢、应激反应和免疫功能的调节中具有重要作用。相比之下，醛固酮在维持水矿物质平衡方面具有重要作用，这些作用是通过MR介导的。硬骨鱼（硬骨鱼，最多样化和进化最新的鱼类）缺乏醛固酮。相比之下，皮质醇在硬骨鱼的水矿物质调节中起着重要作用，传统上被认为是硬骨鱼的主要和最重要的皮质类固醇激素。然而，最近在硬骨鱼中发现了MR。这一发现重新提出了硬骨鱼是否可能拥有特定的盐皮质激素的问题。在本项目中，我们选择了一种进化的方法，以更好地理解脊椎动物中的皮质类固醇信号。利用分子生物学，我们想确定的基因序列的CR在两个遗迹鱼，在脊椎动物进化的关键点分歧，七鳃鳗和bichir。这将使我们能够研究这些激素受体的性质和组织分布，这将使我们能够对这些动物中CRs的可能作用得出初步结论。七鳃鳗是一种无颌鱼类，从5亿年前的有颌脊椎动物分支出来，只有一个CR，其序列部分已知，可以合成皮质醇，但不能合成醛固酮。对七鳃鳗CR序列的分析表明，七鳃鳗和有颌脊椎动物的共同祖先只有一个CR。研究七鳃鳗CR将使我们能够深入了解祖先CR的属性和功能。在有颌脊椎动物的谱系中，祖先的CR基因被复制，产生了祖先的GR和MR。在肉蟹猴（一个包括哺乳动物的系统群）中，这两个基因被保留，但发挥了不同的作用（见上文）。此外，生物合成醛固酮所需的酶一定已经进化。在肉骨鱼的姐妹群--辐鳍鱼中，祖先的GR和MR也被保留了下来，因为它们仍然存在于硬骨鱼中，硬骨鱼是辐鳍鱼的一个衍生亚群。然而，硬骨鱼在进化方面是特殊的，因为在它们的祖先中发生了整个基因组复制，这意味着给定的哺乳动物基因可能有两个硬骨鱼对应物。虽然硬骨鱼后来似乎失去了许多重复的基因，但它们保留了两个GR。我们将研究的CRs在bichir，因为它代表了一个基础的radiopterygian，有分歧之前，硬骨鱼特定的基因组复制。因此，我们预计，bichir有，作为sarcopeans，一个GR和一个MR。我们的问题是在多大程度上的性质和组织分布的bichir CRs类似于那些在少数研究硬骨鱼。由于bichir特殊的进化历史，bichir和所研究的硬骨鱼类之间的相似之处应该适用于大多数硬骨鱼类。