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Department of Organismal Animal Physiology, The Clayton Foundation Laboratories for Peptide Biology, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525AJ Nijmegen, The Netherlands
Search for other papers by Mark O Huising in
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We identified orthologues of all mammalian Janus kinase (JAK) and signal transducer and activator of transcription (STAT) genes in teleostean fishes, indicating that these protein families were already largely complete before the teleost tetrapod split, 450 million years ago. In mammals, the STAT repertoire consists of seven genes (STAT1, -2, -3, -4, -5a, -5b, and -6). Our phylogenetic analyses show that STAT proteins that are recruited downstream of endocrine hormones (STAT3 and STAT5a and -5b) show a markedly higher primary sequence conservation compared with STATs that convey immune signals (STAT1-2, STAT4, and STAT6). A similar dichotomy in evolutionary conservation is observed for the JAK family of protein kinases, which activate STATs. The ligands to activate the JAK/STAT-signalling pathway include hormones and cytokines such as GH, prolactin, interleukin 6 (IL6) and IL12. In this paper, we examine the evolutionary forces that have acted on JAK/STAT signalling in the endocrine and immune systems and discuss the reasons why the JAK/STAT cascade that conveys classical immune signals has diverged much faster compared with endocrine JAK/STAT paralogues.
Search for other papers by Edwin J W Geven in
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Search for other papers by Gert Flik in
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In teleostean fishes the hypothalamic–pituitary–thyroid axis (HPT axis) and the hypothalamic–pituitary–interrenal axis (HPI axis) regulate the release of thyroid hormones (THs) and cortisol respectively. Since many actions of both hormones are involved in the regulation of metabolic processes, communication between both signal pathways can be anticipated. In this study, we describe central and peripheral sites for direct interaction between mediators of both neuroendocrine axes in the common carp (Cyprinus carpio). Despite suggestions in the literature that CRH is thyrotropic in some fish; we were not able to establish stimulatory effects of CRH on the expression of the pituitary TSHβ subunit gene. In preoptic area tissue incubated with 10−7 M thyroxine (T4) a 2.9-fold increase in the expression of CRH-binding protein (CRHBP) was observed. Thus, T4 could reduce the bioavailable hypothalamic crh via the up regulation of crhbp expression and hence down regulate the HPI axis. At the peripheral level, cortisol (10−6 M), ACTH (10−7 M), and α-MSH (10−7 M) stimulate the release of T4 from kidney and head kidney fragments, which contain all functional thyroid follicles in carp, by two- to fourfold. The substantiation of three pituitary thyrotropic factors, viz. TSH, ACTH, and α-MSH, in common carp, allows for an integration of central thyrotropic signals. Clearly, two sites for interaction between the HPT axis, the HPI axis, and α-MSH are present in common carp. These interactions may be key to the proper regulation of general metabolism in this fish.
Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
Search for other papers by Mark O Huising in
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Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
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Department of Cell Biology and Immunology, Wageningen University, Wageningen, The Netherlands
Search for other papers by Gert Flik in
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The class-I helical cytokines constitute a large group of signalling molecules that play key roles in a plethora of physiological processes including host defence, immune regulation, somatic growth, reproduction, food intake and energy metabolism, regulation of neural growth and many more. Despite little primary amino acid sequence similarity, the view that all contemporary class-I helical cytokines have expanded from a single ancestor is widely accepted, as all class-I helical cytokines share a similar three-dimensional fold, signal via related class-I helical cytokine receptors and activate similar intracellular signalling cascades. Virtually all of our knowledge on class-I helical cytokine signalling derives from research on primate and rodent species. Information on the presence, structure and function of class-I helical cytokines in non-mammalian vertebrates and non-vertebrates is fragmentary. Consequently, our ideas about the evolution of this versatile multigene family are often based on a limited comparison of human and murine orthologs. In the last 5 years, whole genome sequencing projects have yielded draft genomes of the early vertebrates, pufferfish (Takifugu rubripes), spotted green pufferfish (Tetraodon nigroviridis) and zebrafish (Danio rerio). Fuelled by this development, fish orthologs of a number of mammalian class-I helical cytokines have recently been discovered. In this review, we have characterised the mammalian class-I helical cytokine family and compared it with the emerging class-I helical cytokine repertoire of teleost fish. This approach offers important insights into cytokine evolution as it identifies the helical cytokines shared by fish and mammals that, consequently, existed before the divergence of teleosts and tetrapods. A ‘fish–mammalian’ comparison will identify the class-I helical cytokines that still await discovery in fish or, alternatively, may have been evolutionarily recent additions to the mammalian cytokine repertoire.
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Department of Animal Physiology, Department of Integrative Biology, Center for Molecular and Biomolecular Informatics (CMBI), The Clayton Foundation Laboratories for Peptide Biology, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
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We describe duplicate leptin genes in zebrafish (Danio rerio) that share merely 24% amino acid identity with each other and only 18% with human leptin. We were also able to retrieve a second leptin gene in medaka (Oryzias latipes). The presence of duplicate leptin genes in these two distantly related teleosts suggests that duplicate leptin genes are a common feature of teleostean fishes. Despite low primary sequence conservation, we are confident in assigning orthology between mammalian and zebrafish leptins for several reasons. First, both zebrafish leptins share their characteristic gene structure and display key features of conserved synteny with mammalian leptin genes. Secondly, the cysteine residues that make up leptin's single disulphide bridge are equally spaced in mammalian and zebrafish leptins and are unique among all members of the class-I helical cytokine family. Thirdly, the zebrafish leptins cluster with other fish leptins and mammalian leptins in phylogenetic analysis, supported by high bootstrap values. Within the leptin cluster, leptin-b forms a separate clade with the leptin-b orthologue from medaka. Finally, our prediction of the tertiary structures shows that both leptins conform to the typical four α-helix bundle structure of the class-I α-helical cytokines. The zebrafish leptins are differentially expressed; the liver shows high leptin-a expression (in concordance with what we observed for carp leptins), while leptin-b is expressed at much lower levels, which are downregulated further upon fasting. The finding of duplicate leptin genes in teleosts adds to our understanding of the evolution of leptin physiology in the early vertebrate lineage.
IGH/UPR, CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 05, France
Department of Animal Physiology, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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IGH/UPR, CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 05, France
Department of Animal Physiology, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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IGH/UPR, CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 05, France
Department of Animal Physiology, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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IGH/UPR, CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 05, France
Department of Animal Physiology, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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IGH/UPR, CNRS 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 05, France
Department of Animal Physiology, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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The mRNA expression of pituitary prolactin (prl), growth hormone (gh), somatolactin (sl), proopiomelanocortin (pomc), and gonadotropins (gthI and gthII) was quantified by real-time PCR, in sea bass, Dicentrarchus labrax, adapted for 1 month to seawater (SW) or freshwater (FW). In addition, IGF-I (igfI) mRNA expression in liver and branchial Na+/K+-ATPase activity were determined. L17 ribosomal protein (rpL17) and elongation factor 1α (ef1α) were validated as reference genes in real-time PCR in the experimental context. The real-time PCR assays were validated for the different hormone genes considered. Expression of pituitary pomc, gthI, gthII, gh, and liver igfI was not significantly different between FW and SW fish. Pituitary prlwas 4.5-foldhigher in FWthan in SW, whereas pituitary sl was 1.8-fold higher in SW- compared with FW-adapted fish. Gill Na+/K+-ATPase specific activity was 2.3-fold higher in FW sea bass compared with SW fish. Plasma cortisol levels were 6.5-fold lower in SW- than in FW-adapted specimens. The results are discussed in relation to the osmoregulatory strategy of this euryhaline SW species, which displays features that do not fit present models based on salmonids and FWeuryhaline teleosts.
Department of Animal Physiology, Departamento de Biología, Instituto de Zoología, Institute for Water and Wetland Research, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
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Department of Animal Physiology, Departamento de Biología, Instituto de Zoología, Institute for Water and Wetland Research, Faculty of Science, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Search for other papers by Luis Vargas-Chacoff in
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The thyroid gland in fish mainly secretes the thyroid prohormone 3,5,3′,5′-tetraiodothyronine (T4), and extrathyroidal outer ring deiodination (ORD) of the prohormone to 3,5,3′-triiodothyronine (T3) is pivotal in thyroid hormone economy. Despite its importance in thyroid hormone metabolism, factors that regulate ORD are still largely unresolved in fish. In addition, the osmoregulatory role of T3 is still a controversial issue in teleosts. In this study, we investigated the regulation of the ORD pathway by cortisol and T3 in different organs (liver, kidney, and gills) of Solea senegalensis and the involvement of T3 in the control of branchial and renal Na+, K+-ATPase activity, a prime determinant of the hydromineral balance in teleosts. Animals were treated with i.p. slow-release coconut oil implants containing cortisol or T3. Hepatic and renal ORD activities were up-regulated in cortisol-injected animals. T3-treated fish showed a prominent decrease in plasma-free T4 levels, whereas ORD activities did not change significantly. Branchial and renal Na+, K+-ATPase activities were virtually unaffected by T3, but were transiently up-regulated by cortisol. We conclude that cortisol regulates local T3 bioavailability in S. senegalensis via ORD in an organ-specific manner. Unlike T3, cortisol appears to be directly implicated in the up-regulation of branchial and renal Na+, K+-ATPase activities.
Search for other papers by Gideon S Bevelander in
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Little is known about vitamin D metabolism in fishes. Several reports have shown hydroxylase activities in various organs to produce vitamin D metabolites, but the enzymes involved have not been isolated or characterized. We isolated and characterized a renal mitochondrial hydroxylase, CYP27A1, that governs vitamin D metabolism in gilthead sea bream, Sparus auratus. The enzyme is highly expressed in kidney and to a far lesser extent in liver. When treated with 25-hydroxy vitamin D or calcitriol, the kidney responded differentially and time dependently with CYP27A1 mRNA expression levels. This response substantiates a role for CYP27A1 in fish vitamin D metabolism. This notion is strengthened by upregulation of CYP27A1 in sea bream treated with parathyroid hormone-related protein (PTHrP), and suggests an original role for PTHrP in calcitriol-regulated processes n fish similar to the role of PTH in mammalian vitamin D-dependent processes.
Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG, Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG, Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG, Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG, Wageningen, The Netherlands
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Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.
Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
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Cell Biology and Immunology Group, Wageningen University, Marijkeweg 40, 6709 PG Wageningen, The Netherlands
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In fish, the hypothalamus–pituitary–interrenal axis (HPI-axis), the equivalent of the hypothalamus–pituitary–adrenal axis (HPA-axis) in mammals, is activated during stress and leads to production and release of cortisol by the interregnal cells in the head kidney. In mammals, the cytokine interleukin-1β (IL-1β) takes a key position in the innate immune and inflammatory responses and influences the HPA-axis. In fish, studies that address the effects of cytokines on HPI-axis activation are limited. We quantitatively assessed expression of IL-1β and its receptor, IL-1RI (the latter was cloned and sequenced), in an acute restraint stress paradigm in common carp, Cyprinus carpio. We also considered expression of the pituitary hormones prolactin (PRL) and GH that have been shown to be structurally related to cytokines and have immunomodulatory actions. Pituitary PRL expression increased fourfold during stress; GH mRNA levels were unaffected. Following restraint, hypothalamic IL-1β expression was upregulated; in head kidney and pituitary pars intermedia, IL-1RI expression significantly increased. We suggest that during acute stress IL-1β signalling in the HPI-axis becomes more sensitive, since both ligand and receptor expressions are enhanced. In vitro, recombinant carp IL-1β stimulates release of α-MSH and N-Ac β-endorphin from the pituitary gland. This observation concurs with increased in vivo plasma levels of α-MSH and N-Ac β-endorphin following restraint. Our findings combined lead us to conclude that IL-1β affects the activity of the HPI-axis and, in turn, expression profiles of genes encoding IL-1β and its receptor are modified during acute stress. Our study provides convincing evidence for bi-directional communication of the HPI-axis and the immune system in fish.
Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Department of Animal Physiology, Cell Biology and Immunology Group, Department of Biochemistry, Radboud University, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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In higher vertebrates, mineralo- (aldosterone) and glucocorticoids (cortisol/corticosterone) exert their multiple actions via specific transcription factors, glucocorticoid (GR) and mineralocorticoid (MR) receptors. Teleostean fishes lack aldosterone and mineral regulatory processes seem under dominant control by cortisol. Despite the absence of the classical mineralocorticoid aldosterone, teleostean fishes do have an MR with cortisol and possibly 11-deoxycorticosterone (DOC) (as alternative for aldosterone) as predominant ligands. We studied corticoid receptors in common carp (Cyprinus carpio L). Through homology cloning and bioinformatic analysis, we found duplicated GR genes and a single MR gene. The GR genes likely result from a major genomic duplication event in the teleostean lineage; we propose that the gene for a second MR was lost. Transactivation studies show that the carp GRs and MR have comparable affinity for cortisol; the MR has significantly higher sensitivity to DOC, and this favours a role for DOC as MR ligand in fish physiology. mRNA of the GRs and the MR is expressed in forebrain (in pallial areas homologous to mammalian hippocampus), corticotrophin-releasing hormone (CRH) cells in the pre-optic nucleus (NPO) and pituitary pars distalis ACTH cells, three key neural/endocrine components of the stress axis. After exposure to prolonged and strong (not to mild acute) stressors, mRNA levels of both GRs and MR become down-regulated in the brain, but not in the NPO CRH cells or pituitary ACTH cells. Our data predicts a function in stress physiology for all CRs and suggest telencephalon as a first line cortisol target in stress.
