Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken

Abstract

BackgroundParathyroid 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.ResultsThe 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.ConclusionsThe 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.

Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken

“…Human PTH activated chicken PTH1R and stimulated cAMP production with an apparently similar potency to chicken PTHrP. Interestingly, chicken PTH-L had a low capacity to activate any of the receptors, which is consistent with its lower potency in stimulating calcium transport across the CAM [2]. Whether PTH-L binds to another as yet unidentified receptor(s) or is a less active PTH-family member in chicken remains to be established.…”

“…heart, mammary gland and immune system), which are mediated by calcium [1,2]. PTH, PTH-related protein (PTHrP) and the tuberoinfundibular peptide 39 (TIP39 a.k.a.…”

Twenty-five years of PTHrP progress: From cancer hormone to multifunctional cytokine

“…If conservation across species is evidence of gene importance, PTHrP prevails – fugu fish PTH has 44% identity with human PTH whereas fugu fish PTHrP bears 53% similarity with human PTHrP (25). At the amino acid level, chicken PTH shares 88% similarity with human, and chicken PTHrP shares 91% similarity with human (26). The first 111 amino acids of PTHrP are extraordinarily conserved among many species.…”

“…In fish, PTH produced in the gills is responsible for local calcium regulation; whereas via evolution to tetrapods the parathyroid gland assumed an endocrine role as calcium requirements shifted from an aquatic to a terrestrial environment (27). PTHrP, having a fairly simple gene structure in lower vertebrates acquired a more complex structure with added exons and alternative promoters with progression to humans, and in parallel picked up a stronger paracrine emphasis (26;28). …”

Parathyroid Hormone-Related Protein and Prostate Cancer

“…ПТГрП входит в семейство паратиреоидного гормона (ПТГ), состоящего из группы структурно-родствен-ных биологически активных факторов, участву-ющих в регуляции кальциевого и костного гоме-остаза и процессов развития различных тканей и органов [31, 63,52]. ПТГ и ПТГрП оказывают в основном идентичные эффекты на клетки-мише-ни классического ПТГ, но их влияние на другие клетки-мишени существенно различается.…”