Parathyroid hormone gene family in a cartilaginous fish, the elephant shark (Callorhinchus milii)

Abstract

The development of bone was a major step in the evolution of vertebrates. A bony skeleton provided structural support and a calcium reservoir essential for the movement from an aquatic to a terrestrial environment. Cartilaginous fishes are the oldest living group of jawed vertebrates. In this study we have identified three members of the parathyroid hormone (Pth) gene family in a cartilaginous fish, the elephant shark (Callorhinchus milii). The three genes include two Pth genes, designated as Pth1 and Pth2, and a Pthrp gene. Phylogenetic analysis suggested that elephant shark Pth2 is an ancient gene whose orthologue is lost in bony vertebrates. The Pth1 and Pth2 genes have the same structure as the Pth gene in bony vertebrates, whereas the structure of the Pthrp gene is more complex in tetrapods compared with elephant shark. The three elephant shark genes showed distinct patterns of expression, with Pth2 being expressed only in the brain and spleen. This contrasts with localization of the corresponding proteins, which showed considerable overlap in their distribution. There were conserved sites of localization for Pthrp between elephant shark and mammals, including tissues such as kidney, skin, skeletal and cardiac muscle, pancreas, and cartilage. The elephant shark Pth1(1-34) and Pthrp(1-34) peptides were able to stimulate cAMP accumulation in mammalian UMR106.01 cells. However, Pth2(1-34) peptide did not show such PTH-like biologic activity. The presence of Pth and Pthrp genes in the elephant shark indicates that these genes played fundamental roles before their recruitment to bone development in bony jawed vertebrates. ß

Evolution of Parathyroid Hormone Receptor Family and Their Ligands in Vertebrate

“…Consistent with the “4:1 rule” (27, 28), except for the loss of the fourth putative PTHR, all the homologs of PTH and the PTHR genes could be identified in elephant shark (hereafter abbreviated to “e”) (17, 29). PTH, PTHrP, and putative ePTH-L (designated as PTH2 in the references) have already been cloned, while a putative tip39 gene was identified in the genome database (17, 29). Even though ePTH2 is phylogenetically grouped with other PTH-Ls, the identity of ePTH2 as an ortholog to fish PTH-L was questioned because the gene structure of ePTH2 is different from teleost pth-l , but resembles other pth genes.…”

“…Even though ePTH2 is phylogenetically grouped with other PTH-Ls, the identity of ePTH2 as an ortholog to fish PTH-L was questioned because the gene structure of ePTH2 is different from teleost pth-l , but resembles other pth genes. Elephant shark pth2 has its first intron before the KR cleavage site; whereas teleost pth-l genes do not contain this cleavage site, and instead have the first intron before the SRR motif (29). More importantly, ePTH2 is unable to stimulate cAMP production in PTH1R expressing cells, but teleost PTH-L appears to be a potent factor (29).…”

“…Elephant shark pth2 has its first intron before the KR cleavage site; whereas teleost pth-l genes do not contain this cleavage site, and instead have the first intron before the SRR motif (29). More importantly, ePTH2 is unable to stimulate cAMP production in PTH1R expressing cells, but teleost PTH-L appears to be a potent factor (29). …”

Vitamin D: calcium and bone homeostasis during evolution

“…The full hormonal vitamin D system and FGF23 first appeared in fish. The parathyroid glands, however, are only startedin amphibians, but nevertheless two PTH genes and one PTrP gene were already identified in cartilaginous (the elephant shark 90 ) and bony fish (Takifugu rubripes 91 ). The overall gene structure of these fish PTH family members closely resembles that of higher vertrebrate species.…”

“…102 Parathyroid glands first appeared during evolution in amphibians but PTH genes are widely expressed in most tissues of fish. 90 PTH receptors are older and were already used for signaling of PTHrP, which functions as a major paracrine factor 103 and can also act as a hypercalcemic factor in early vertebrates. PTHrP is already present in cartilaginous sharks and rays 104 but a pituitary factor, probably prolactin or somatolactin, is the major hypercalcemic factor in fish.…”