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Evolution of primary hemostasis in early vertebrates.

ABSTRACT: Hemostasis is a defense mechanism which protects the organism in the event of injury to stop bleeding. Recently, we established that all the known major mammalian hemostatic factors are conserved in early vertebrates. However, since their highly vascularized gills experience high blood pressure and are exposed to the environment, even very small injuries could be fatal to fish. Since trypsins are forerunners for coagulation proteases and are expressed by many extrapancreatic cells such as endothelial cells and epithelial cells, we hypothesized that trypsin or trypsin-like proteases from gill epithelial cells may protect these animals from gill bleeding following injuries. In this paper we identified the release of three different trypsins from fish gills into water under stress or injury, which have tenfold greater serine protease activity compared to bovine trypsin. We found that these trypsins activate the thrombocytes and protect the fish from gill bleeding. We found 27 protease-activated receptors (PARs) by analyzing zebrafish genome and classified them into five groups, based on tethering peptides, and two families, PAR1 and PAR2, based on homologies. We also found a canonical member of PAR2 family, PAR2-21A which is activated more readily by trypsin, and PAR2-21A tethering peptide stops gill bleeding just as trypsin. This finding provides evidence that trypsin cleaves a PAR2 member on thrombocyte surface. In conclusion, we believe that the gills are evolutionarily selected to produce trypsin to activate PAR2 on thrombocyte surface and protect the gills from bleeding. We also speculate that trypsin may also protect the fish from bleeding from other body injuries due to quick contact with the thrombocytes. Thus, this finding provides evidence for the role of trypsins in primary hemostasis in early vertebrates.

SUBMITTER: Kim S

PROVIDER: S-EPMC2793433 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Evolution of primary hemostasis in early vertebrates.

Kim Seongcheol S Carrillo Maira M Kulkarni Vrinda V Jagadeeswaran Pudur P

PloS one 20091223 12

Hemostasis is a defense mechanism which protects the organism in the event of injury to stop bleeding. Recently, we established that all the known major mammalian hemostatic factors are conserved in early vertebrates. However, since their highly vascularized gills experience high blood pressure and are exposed to the environment, even very small injuries could be fatal to fish. Since trypsins are forerunners for coagulation proteases and are expressed by many extrapancreatic cells such as endoth ...[more]

PMID: 20037653

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Project description:BACKGROUND: Forkhead box, class O (FoxO) belongs to the large family of forkhead transcription factors that are characterized by a conserved forkhead box DNA-binding domain. To date, the FoxO group has four mammalian members: FoxO1, FoxO3a, FoxO4 and FoxO6, which are orthologs of DAF16, an insulin-responsive transcription factor involved in regulating longevity of worms and flies. The degree of homology between these four members is high, especially in the forkhead domain, which contains the DNA-binding interface. Yet, mouse FoxO knockouts have revealed that each FoxO gene has its unique role in the physiological process. Whether the functional divergences are primarily due to adaptive selection pressure or relaxed selective constraint remains an open question. As such, this study aims to address the evolutionary mode of FoxO, which may lead to the functional divergence. RESULTS: Sequence similarity searches have performed in genome and scaffold data to identify homologues of FoxO in vertebrates. Phylogenetic analysis was used to characterize the family evolutionary history by identifying two duplications early in vertebrate evolution. To determine the mode of evolution in vertebrates, we performed a rigorous statistical analysis with FoxO gene sequences, including relative rate ratio tests, branch-specific dN/dS ratio tests, site-specific dN/dS ratio tests, branch-site dN/dS ratio tests and clade level amino acid conservation/variation patterns analysis. Our results suggest that FoxO is constrained by strong purifying selection except four sites in FoxO6, which have undergone positive Darwinian selection. The functional divergence in this family is best explained by either relaxed purifying selection or positive selection. CONCLUSION: We present a phylogeny describing the evolutionary history of the FoxO gene family and show that the genes have evolved through duplications followed by purifying selection except for four sites in FoxO6 fixed by positive selection lie mostly within the non-conserved optimal PKB motif in the C-terminal part. Relaxed selection may play important roles in the process of functional differentiation evolved through gene duplications as well.

Project description:BackgroundCide family proteins including Cidea, Cideb and Cidec/Fsp27, contain an N-terminal CIDE-N domain that shares sequence similarity to the N-terminal CAD domain (NCD) of DNA fragmentation factors Dffa/Dff45/ICAD and Dffb/Dff40/CAD, and a unique C-terminal CIDE-C domain. We have previously shown that Cide proteins are newly emerged regulators closely associated with the development of metabolic diseases such as obesity, diabetes and liver steatosis. They modulate many metabolic processes such as lipolysis, thermogenesis and TAG storage in brown adipose tissue (BAT) and white adipose tissue (WAT), as well as fatty acid oxidation and lipogenesis in the liver.ResultsTo understand the evolutionary process of Cide proteins and provide insight into the role of Cide proteins as potential metabolic regulators in various species, we searched various databases and performed comparative genomic analysis to study the sequence conservation, genomic structure, and phylogenetic tree of the CIDE-N and CIDE-C domains of Cide proteins. As a result, we identified signature sequences for the N-terminal region of Dffa, Dffb and Cide proteins and CIDE-C domain of Cide proteins, and observed that sequences homologous to CIDE-N domain displays a wide phylogenetic distribution in species ranging from lower organisms such as hydra (Hydra vulgaris) and sea anemone (Nematostella vectensis) to mammals, whereas the CIDE-C domain exists only in vertebrates. Further analysis of their genomic structures showed that although evolution of the ancestral CIDE-N domain had undergone different intron insertions to various positions in the domain among invertebrates, the genomic structure of Cide family in vertebrates is stable with conserved intron phase.ConclusionBased on our analysis, we speculate that in early vertebrates CIDE-N domain was evolved from the duplication of NCD of Dffa. The CIDE-N domain somehow acquired the CIDE-C domain that was formed around the same time, subsequently generating the Cide protein. Subsequent duplication and evolution have led to the formation of different Cide family proteins that play unique roles in the control of metabolic pathways in different tissues.

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Evolution of primary hemostasis in early vertebrates.

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Evolution of primary hemostasis in early vertebrates.

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