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BMC Evol Biol
2010 May 06;10:373. doi: 10.1186/1471-2148-10-373.
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Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken.
Pinheiro PL
,
Cardoso JC
,
Gomes AS
,
Fuentes J
,
Power DM
,
Canário AV
.
???displayArticle.abstract??? Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) belong to a family of endocrine factors that share a highly conserved N-terminal region (amino acids 1-34) and play key roles in calcium homeostasis, bone formation and skeletal development. Recently, PTH-like peptide (PTH-L) was identified in teleost fish raising questions about the evolution of these proteins. Although PTH and PTHrP have been intensively studied in mammals their function in other vertebrates is poorly documented. Amphibians and birds occupy unique phylogenetic positions, the former at the transition of aquatic to terrestrial life and the latter at the transition to homeothermy. Moreover, both organisms have characteristics indicative of a complex system in calcium regulation. This study investigated PTH family evolution in vertebrates with special emphasis on Xenopus and chicken. The PTH-L gene is present throughout the vertebrates with the exception of placental mammals. Gene structure of PTH and PTH-L seems to be conserved in vertebrates while PTHrP gene structure is divergent and has acquired new exons and alternative promoters. Splice variants of PTHrP and PTH-L are common in Xenopus and chicken and transcripts of the former have a widespread tissue distribution, although PTH-L is more restricted. PTH is widely expressed in fish tissue but from Xenopus to mammals becomes largely restricted to the parathyroid gland. The N-terminal (1-34) region of PTH, PTHrP and PTH-L in Xenopus and chicken share high sequence conservation and the capacity to modify calcium fluxes across epithelia suggesting a conserved role in calcium metabolism possibly via similar receptors. The parathyroid hormone family contains 3 principal members, PTH, PTHrP and the recently identified PTH-L. In teleosts there are 5 genes which encode PTHrP (2), PTH (2) and PTH-L and in tetrapods there are 3 genes (PTHrP, PTH and PTH-L), the exception is placental mammals which have 2 genes and lack PTH-L. It is hypothesized that genes of the PTH family appeared at approximately the same time during the vertebrate radiation and evolved via gene duplication/deletion events. PTH-L was lost from the genome of eutherian mammals and PTH, which has a paracrine distribution in lower vertebrates, became the product of a specific endocrine tissue in Amphibia, the parathyroid gland. The PTHrP gene organisation diverged and became more complex in vertebrates and retained its widespread tissue distribution which is congruent with its paracrine nature.
Figure 1. Multiple sequence alignment of the Xenopus and chicken 1-34 PTH family members mature peptide N-terminal region with teleost (Takifugu and zebrafish) and mammals (human and mouse). Conserved amino acid positions identified in all vertebrates are indicated by "*" and percentage of sequence similarity in comparison with human PTH and PTHrP and Takifugu PTH-L is given. The typical three amino acid motifs characteristic of each PTH family member in positions 8 to 10 are indicated in black. % similarity to first sequence is indicated on the right. Accession number of the sequences used were: Human (PTH, AAH96144.1; PTHrP, AAA60216); Mouse (PTH, NP_065648; PTHrP, CAC39218.1); Zebrafish (PTHA, NP_998115.1; PTHB, NP_998114.1; PTHrPA, AAY87956.1; PTHrPB, AAY87957.1; PTH-L, CU856139); Takifugu (PTHA, CAG26460.1; PTHB, CAG26461.1; PTHrPA, CAB94712.1; PTHrPB, CAG26459.2; PTH-L, CAG26462.1).
Figure 2. Gene organization of the vertebrate PTH-like family members. Exons are represented by boxes and lines indicate introns. Coding (E1 to E4) and non-coding (E1' to E'3) exons are numbered and annotated in bold and italics, respectively. Dotted-filled boxes represent the mature coding regions and black lines box the signal peptide sequence. Arrows represent alternative splice isoforms identified in Xenopus and chicken and previously reported in human. The general organization of the conserved vertebrate PTH gene structure is represented and the size of vertebrate PTHrP and PTH-L precursors is given (amino acids). The length of the chicken PTH-L precursor was predicted in silico and is indicated in italics. Dashed lines indicate incomplete structures that were not confirmed in silico or amplified by RT-PCR. The start of the mature peptide (+1) and the size of the signal peptide for all vertebrate PTH family members is indicated. The localization of the human PTHrP promoter regions (P1, P2 and P3) and the chicken PTHrP putative promoter sites (P1', P2' and P3') and TATA box consensus sequence within the region of P3' are shown. The figure is not drawn to scale and Takifugu A structure was taken from Power et al. [42].
Figure 3. Consensus phylogenetic tree of Xenopus and chicken PTH family members using the Neighbor Joining method [60]and 1000 bootstraps replicates with the complete amino acid precursor sequence in Mega3.1 software [61]with the settings pairwise deletion, p-distance model and 222 informative sites. Xenopus and chicken PTH family members are in italics and the sequence of human GIP (HsaGIP, NP_004114) was used as outgroup. Human (NP_848544), mouse (NP_444486) and zebrafish (NP_991140) TIP39 mature protein sequences were included for comparative purposes. The accession numbers of other sequences utilized for tree construction are indicated in Figure 1 and seabream PTHrP is AAF79073.
Figure 4. Short-range gene linkage comparisons of the PTH family members in the Takifugu, Xenopus, chicken and human genomes. Genes are represented by closed boxes and the size of the chromosome region analysed is given underneath. Genes were named using HUGO and lines indicate chromosome/scaffold segments. The vertebrate PTH family members are in bold and conserved flanking genes identified within the homologue regions are underlined. The PTH gene is localized in Xenopus scaffold_235 and in chicken chromosome 5 and two conserved genes ARNTL and BTBD10 were identified. The Xenopus and chicken PTHrP maps to scaffold_766 and chromosome 1, respectively and the gene MRPS35 was found in close proximity in all vertebrate regions analysed. PTH-L and SFRS3 genes map to Xenopus scaffold_169 and to chicken chromosome 26. SFRS3 was not linked to Takifugu PTH-L and is present on human chromosome 6 which lacks PTH-L. For simplicity, only genes with correspondence across species are represented. The figure is not drawn to scale.
Figure 5. Expression of chicken (open bars) and Xenopus (closed bars) PTH family genes as determined by q-PCR. Gene specific primers were used to amplify PTH and PTH-L transcripts and PTHrP spliced isoforms from several tissues. The number of amplified transcripts is presented in relation to 18S copy number and data is presented as mean ± S.E. (n = 2 to 3 for Xenopus and n = 3 for chicken except for pituitary where n = 1).
Figure 6. Calcium fluxes (water to blood side) in Xenopus abdominal skin and chicken 16 to 18 day old embryo CAM (shell to embryo side) after the addition of 10 nM, N-terminal (1-34) PTH, PTHrP and PTH-L to the basolateral membrane site. Human PTH (1-34) and salmon Luteinizing hormone-releasing hormone (LHRH) were used as positive and negative controls respectively. Results are shown as mean ± SEM and the "*" indicates statistical significance compared to control (time 0) (p < 0.05).
Abbink,
Parathyroid hormone-related protein in teleost fish.
2007, Pubmed
Abbink,
Parathyroid hormone-related protein in teleost fish.
2007,
Pubmed
Altschul,
Basic local alignment search tool.
1990,
Pubmed
Balabanova,
Distribution and concentration of immunoreactive parathyroid hormone in brain and pituitary of sheep.
1985,
Pubmed
Bergwitz,
Identification, functional characterization, and developmental expression of two nonallelic parathyroid hormone (PTH)/PTH-related peptide receptor isoforms in Xenopus laevis (Daudin).
1998,
Pubmed
,
Xenbase
Canario,
Novel bioactive parathyroid hormone and related peptides in teleost fish.
2006,
Pubmed
Cortelyou,
Parathyroid glands of amphibians. I. Parathyroid structure and function in the amphibian, with emphasis on regulation of mineral ions in body fluids.
1967,
Pubmed
Danks,
Parathyroid hormone-related protein in tissues of the emerging frog (Rana temporaria): immunohistochemistry and in situ hybridisation.
1997,
Pubmed
Danks,
Identification of a parathyroid hormone in the fish Fugu rubripes.
2003,
Pubmed
Farquharson,
Regulation of chondrocyte terminal differentiation in the postembryonic growth plate: the role of the PTHrP-Indian hedgehog axis.
2001,
Pubmed
Fuentes,
Parathyroid hormone-related protein regulates intestinal calcium transport in sea bream (Sparus auratus).
2006,
Pubmed
Gensure,
Parathyroid hormone and parathyroid hormone-related peptide, and their receptors.
2005,
Pubmed
Gensure,
Identification and characterization of two parathyroid hormone-like molecules in zebrafish.
2004,
Pubmed
Graves,
Embryonic chick allantois: functional isolation and development of sodium transport.
1986,
Pubmed
Guerreiro,
The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish.
2007,
Pubmed
Günther,
Genetic ablation of parathyroid glands reveals another source of parathyroid hormone.
2000,
Pubmed
Habener,
Biosynthesis of parathyroid hormone.
1976,
Pubmed
Hamburger,
A series of normal stages in the development of the chick embryo. 1951.
1992,
Pubmed
Ieda,
Changes in parathyroid hormone-related peptide receptor binding in the shell gland of laying hens (Gallus domesticus) during the oviposition cycle.
2000,
Pubmed
Ingleton,
Distribution and functions of parathyroid hormone-related protein in vertebrate cells.
1996,
Pubmed
Jaillon,
Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype.
2004,
Pubmed
Jin,
Evaluation of the purity of recombinant proteins and detection of residual protein contaminants via N-terminal microsequencing and database searching.
1991,
Pubmed
John,
Identification and characterization of the murine and human gene encoding the tuberoinfundibular peptide of 39 residues.
2002,
Pubmed
Jüppner,
A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide.
1991,
Pubmed
Khosla,
Nucleotide sequence of cloned cDNAs encoding chicken preproparathyroid hormone.
1988,
Pubmed
KOEFOED-JOHNSEN,
The nature of the frog skin potential.
1958,
Pubmed
Kreth,
Differential expression of 5'-UTR splice variants of the adenosine A2A receptor gene in human granulocytes: identification, characterization, and functional impact on activation.
2008,
Pubmed
Kumar,
MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment.
2004,
Pubmed
Laverty,
PTH stimulates a Cl(-)-dependent and EIPA-sensitive current in chick proximal tubule cells in culture.
2003,
Pubmed
Martyniuk,
Seasonal relationship between gonadotropin, growth hormone, and estrogen receptor mRNA expression in the pituitary gland of largemouth bass.
2009,
Pubmed
Medill,
Parathyroid hormone-related peptide expression in the epiphyseal growth plate of the juvenile chicken: evidence for the origin of the parathyroid hormone-related peptide found in the epiphyseal growth plate.
2001,
Pubmed
Mignone,
Untranslated regions of mRNAs.
2002,
Pubmed
Minina,
Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.
2002,
Pubmed
Moseley,
Parathyroid hormone-related protein.
1995,
Pubmed
Murray,
Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands.
2005,
Pubmed
Okabe,
The origin of the parathyroid gland.
2004,
Pubmed
Orloff,
Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions.
1994,
Pubmed
Packard,
The effect of calcium-regulating hormones on transport of calcium across the chorioallantoic membrane of the chicken embryo.
1998,
Pubmed
Pang,
Parathyroid hormone-like immunoreactivity in brains of tetrapod vertebrates.
1988,
Pubmed
Pang,
Immunocytochemical distribution of PTH immunoreactivity in vertebrate brains.
1988,
Pubmed
Papasani,
Identification and characterization of the zebrafish and fugu genes encoding tuberoinfundibular peptide 39.
2004,
Pubmed
Philbrick,
Defining the roles of parathyroid hormone-related protein in normal physiology.
1996,
Pubmed
Potts,
Parathyroid hormone: past and present.
2005,
Pubmed
Power,
Genomic structure and expression of parathyroid hormone-related protein gene (PTHrP) in a teleost, Fugu rubripes.
2000,
Pubmed
Rodriguez-Commes,
Parathyroid hormone stimulates electrogenic sodium transport in A6 cells.
1995,
Pubmed
,
Xenbase
Rosenberg,
Renal and adrenal adenosine 3',5'-monophosphate production and corticosteroid secretion in response to synthetic chicken parathyroid hormone-(1-34).
1989,
Pubmed
Rotllant,
Calcium mobilization from fish scales is mediated by parathyroid hormone related protein via the parathyroid hormone type 1 receptor.
2005,
Pubmed
Rotllant,
Stimulation of cortisol release by the N terminus of teleost parathyroid hormone-related protein in interrenal cells in vitro.
2005,
Pubmed
Rotllant,
Ligand binding and signalling pathways of PTH receptors in sea bream (Sparus auratus) enterocytes.
2006,
Pubmed
Rubin,
Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide.
1999,
Pubmed
Rubin,
A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones.
1999,
Pubmed
Russell,
Nucleotide sequence of the DNA complementary to avian (chicken) preproparathyroid hormone mRNA and the deduced sequence of the hormone precursor.
1989,
Pubmed
Safer,
A topical parathyroid hormone/parathyroid hormone-related peptide receptor antagonist stimulates hair growth in mice.
2007,
Pubmed
Saitou,
The neighbor-joining method: a new method for reconstructing phylogenetic trees.
1987,
Pubmed
Schermer,
Functional properties of a synthetic chicken parathyroid hormone-related protein 1-36 fragment.
1994,
Pubmed
Shimizu,
Minimization of parathyroid hormone. Novel amino-terminal parathyroid hormone fragments with enhanced potency in activating the type-1 parathyroid hormone receptor.
2000,
Pubmed
Srivastav,
Amphibian parathyroids: morphological and functional aspects.
1995,
Pubmed
Stiffler,
Responses of frog skin, Rana pipiens, calcium ion transport to parathyroid hormone, calcitonin, and vitamin D3.
1998,
Pubmed
Thiede,
Nucleotide sequence of a parathyroid hormone-related peptide expressed by the 10 day chicken embryo.
1990,
Pubmed
Thompson,
The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools.
1997,
Pubmed
Usdin,
TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus.
1999,
Pubmed
Zhao,
Expression of parathyroid hormone-related peptide (PthrP) and its receptor (PTH1R) during the histogenesis of cartilage and bone in the chicken mandibular process.
2002,
Pubmed
Zuscik,
Parathyroid hormone-related peptide regulation of chick tibial growth plate chondrocyte maturation requires protein kinase A.
2002,
Pubmed
