Abstract
The parathyroid hormone (PTH) family is a group of structurally-related secreted peptides involved in bone mineral homeostasis and multitude of developmental processes in vertebrates. These peptides mediate actions through PTH receptors (PTHRs), which belong to the transmembrane G protein-coupled receptor group. To date, genes encoding for PTH and PTHR have only been identified in chordates, suggesting that this signaling pathway may be an evolutionary innovation of our phylum. In vertebrates, we found up to six PTH and three PTHR different paralogs, varying in number between mammals and teleost fishes due to the different rounds of whole-genome duplication and specific gene losses suffered between the two groups of animals. The diversification of the PTH gene family has been accompanied by both functional divergence and convergence, making sometimes difficult the comparison between PTH peptides of teleosts and mammals. Here, we review the roles of all Pth peptides in fishes, and based on the evolutionary history of PTH paralogs, we propose a new and simple nomenclature from PTH1 to PTH4. Moreover, the recent characterization of the Pth4 in zebrafish allows us to consider the prominent role of the brain-to-bone signaling pathway in the regulation of bone development and homeostasis. Finally, comparison between PTH peptides of fish and mammals allows us to discuss an evolutionary model for PTH functions related to bone mineral balance during the vertebrate transition from an aquatic to a terrestrial environment.
Highlights
One of the innovative features that characterize vertebrates is the bone, a stiff tissue with high capacity for regeneration
Mammals have two genes that code for PTH receptors (PTHRs) within the class B G protein-coupled receptors (GPCRs) (Venkatakrishnan et al, 2013), which has been termed as “parathyroid hormone type I or II receptor” (PTH1R, PTH2R)
The PTH family in fishes has acquired a higher complexity, consisting on at least six genes resulting from the extra-round of whole-genome duplication (WGD) occurred at the base of the teleost lineage: two Pth paralogs (Ptha/Pthb), two Pthlh (Pthlha/Pthlhb), Tip39(Pth2) and a new PTH-like peptide named Pth4 (Guerreiro et al, 2007; SuarezBregua et al, 2017)
Summary
One of the innovative features that characterize vertebrates is the bone, a stiff tissue with high capacity for regeneration. The evolution of bone has been accompanied by the development of a hormonal system that allows a precise control of bone mineral metabolism Within this system, the parathyroid hormone (PTH) family of peptides plays key roles in the homeostasis of calcium-phosphate that act as regulators in numerous biological processes, such as the formation of hydroxyapatite crystals for bone mineralization (Potts, 2005; McCauley and Martin, 2012). There are three known genes that code for PTH peptides, which classically has been termed as “parathyroid hormone” (PTH), “parathyroid hormone related protein or PTH-like hormone” (PTHrP, PTHLH), and “tuberoinfundibular peptide of 39” (TIP39, PTH2). Mammals have two genes that code for PTHRs within the class B G protein-coupled receptors (GPCRs) (Venkatakrishnan et al, 2013), which has been termed as “parathyroid hormone type I or II receptor” (PTH1R, PTH2R). PTH is secreted by the parathyroid gland (PTG), which functions as the major endocrine regulator of the calcium-phosphate metabolism
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