Evolution of corticosteroid receptor signalling pathways in vertebrates

类固醇激素受体是介导类固醇激素作用的蛋白质。就像一把锁和钥匙一样，任何给定的受体只结合一种或几种相似的激素。类固醇与其受体的结合诱导受体-激素复合物进入细胞核。在这里，复合物结合到目标基因的特定序列，其表达反过来被调节。因此，类固醇受体可以被视为细胞开关，通过类固醇激素打开或关闭基因表达。性类固醇有特定的受体，包括雌激素、雄激素和黄体酮，以及肾上腺皮质合成的类固醇，也被称为皮质类固醇，包括皮质醇和醛固酮。本项目主要研究皮质类固醇受体的进化。在包括人类在内的哺乳动物中，存在两种皮质类固醇受体（CRs）：糖皮质激素受体（GR）和矿皮质激素受体（MR）。皮质醇通过GR起作用，在调节机体一般代谢、应激反应和免疫功能等方面具有重要作用。相比之下，醛固酮在维持水矿物质平衡中起着重要作用，而这些作用是通过硬骨鱼（硬骨鱼，最多样化和进化最晚的鱼类群）缺乏醛固酮而介导的。相比之下，皮质醇在硬骨鱼的水矿物调节中起着重要作用，传统上被认为是硬骨鱼主要和最重要的皮质类固醇激素。然而，最近在硬鱼身上发现了核磁共振。这一发现再次引发了硬骨鱼是否可能拥有一种特定的矿物皮质激素的问题。在目前的项目中，我们选择了一种进化的方法来更好地理解脊椎动物的皮质类固醇信号。利用分子生物学的方法，我们想要确定在脊椎动物进化的关键时刻分化的两种遗迹鱼类——七鳃鳗和双头鱼的CRs基因序列。这将使我们能够研究这些激素受体的特性和组织分布，从而初步得出CRs在这些动物中的可能作用。七鳃鳗是一种无颌鱼类，从500万年前的有颌脊椎动物分化而来，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基因序列的分析表明，七鳃鳗和颌类脊椎动物的共同祖先只有一个CR基因，研究七鳃鳗CR基因将有助于我们了解祖先CR基因的特性和功能，在导致颌类脊椎动物的谱系中，祖先CR基因的复制产生了祖先GR和mr基因，而在包括哺乳动物在内的系统类群中，这两个基因被保留下来。但采用了不同的角色（见上文）。此外，生物合成醛固酮所需的酶一定已经进化了。在放光鳍鱼类（鳍状鱼类）中，祖先的GR和MR也被保留，因为它们仍然存在于放光鳍鱼类的衍生亚群硬骨鱼中。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全基因组复制，这意味着一个给定的哺乳动物基因可能有两个对应的硬骨鱼。虽然硬骨鱼后来似乎失去了许多复制基因，但它们保留了两个gr。我们将研究bichir中的CRs，因为它代表了一个基础的放光鳍鱼，在硬骨鱼特异性基因组复制之前已经分化。因此，我们预计，作为硬骨鱼，双鳃鱼有一个GR和一个mr。我们的问题是，双鳃鱼的cr的性质和组织分布与少数研究过的硬骨鱼有多相似。由于bichir的特殊进化历史，bichir和所研究的硬骨鱼之间的相似性应该适用于大多数硬骨鱼。

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.