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FASEB J
2017 Feb 01;312:569-583. doi: 10.1096/fj.201600815R.
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Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.
Suarez-Bregua P
,
Torres-Nuñez E
,
Saxena A
,
Guerreiro P
,
Braasch I
,
Prober DA
,
Moran P
,
Cerda-Reverter JM
,
Du SJ
,
Adrio F
,
Power DM
,
Canario AV
,
Postlethwait JH
,
Bronner ME
,
Cañestro C
,
Rotllant J
.
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Regulation of bone development, growth, and remodeling traditionally has been thought to depend on endocrine and autocrine/paracrine modulators. Recently, however, brain-derived signals have emerged as key regulators of bone metabolism, although their mechanisms of action have been poorly understood. We reveal the existence of an ancient parathyroid hormone (Pth)4 in zebrafish that was secondarily lost in the eutherian mammals' lineage, including humans, and that is specifically expressed in neurons of the hypothalamus and appears to be a central neural regulator of bone development and mineral homeostasis. Transgenic fish lines enabled mapping of axonal projections leading from the hypothalamus to the brainstem and spinal cord. Targeted laser ablation demonstrated an essential role for of pth4-expressing neurons in larval bone mineralization. Moreover, we show that Runx2 is a direct regulator of pth4 expression and that Pth4 can activate cAMP signaling mediated by Pth receptors. Finally, gain-of-function experiments show that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Based on our discovery and characterization of Pth4, we propose a model for evolution of bone homeostasis in the context of the vertebrate transition from an aquatic to a terrestrial lifestyle.-Suarez-Bregua, P., Torres-Nuñez, E., Saxena, A., Guerreiro, P., Braasch, I., Prober, D. A., Moran, P., Cerda-Reverter, J. M., Du, S. J., Adrio, F., Power, D. M., Canario, A. V. M., Postlethwait, J. H., Bronner, M E., Cañestro, C., Rotllant, J. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.
Abbink,
PTHrP regulation and calcium balance in sea bream (Sparus auratus L.) under calcium constraint.
2006, Pubmed
Abbink,
PTHrP regulation and calcium balance in sea bream (Sparus auratus L.) under calcium constraint.
2006,
Pubmed
Albalat,
Evolution by gene loss.
2016,
Pubmed
Anjos,
PTHrP-induced modifications of the sea bream (Sparus auratus) vertebral bone proteome.
2013,
Pubmed
Bajayo,
Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual.
2012,
Pubmed
Bhattacharya,
Evolution of the vertebrate pth2 (tip39) gene family and the regulation of PTH type 2 receptor (pth2r) and its endogenous ligand pth2 by hedgehog signaling in zebrafish development.
2011,
Pubmed
Blair,
The developmental basis of skeletal cell differentiation and the molecular basis of major skeletal defects.
2008,
Pubmed
Canario,
Novel bioactive parathyroid hormone and related peptides in teleost fish.
2006,
Pubmed
Cartharius,
MatInspector and beyond: promoter analysis based on transcription factor binding sites.
2005,
Pubmed
Catchen,
Conserved synteny and the zebrafish genome.
2011,
Pubmed
Catchen,
Automated identification of conserved synteny after whole-genome duplication.
2009,
Pubmed
Cañestro,
Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes.
2009,
Pubmed
Cerdá-Reverter,
Peptide YY (PYY) and fish pancreatic peptide Y (PY) expression in the brain of the sea bass (Dicentrarchus labrax) as revealed by in situ hybridization.
2000,
Pubmed
Chen,
A colorimetric assay for measuring activation of Gs- and Gq-coupled signaling pathways.
1995,
Pubmed
Christov,
Insights from genetic disorders of phosphate homeostasis.
2013,
Pubmed
Dehal,
Two rounds of whole genome duplication in the ancestral vertebrate.
2005,
Pubmed
Driessler,
Hypothalamic regulation of bone.
2010,
Pubmed
Elefteriou,
Regulation of bone remodeling by the central and peripheral nervous system.
2008,
Pubmed
Flores,
A hierarchy of Runx transcription factors modulate the onset of chondrogenesis in craniofacial endochondral bones in zebrafish.
2006,
Pubmed
Galitzer,
Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion.
2008,
Pubmed
Gardella,
Molecular properties of the PTH/PTHrP receptor.
2001,
Pubmed
Gensure,
Identification and characterization of two parathyroid hormone-like molecules in zebrafish.
2004,
Pubmed
Goretti Penido,
Phosphate homeostasis and its role in bone health.
2012,
Pubmed
Graham,
Characterization of a type IIb sodium-phosphate cotransporter from zebrafish (Danio rerio) kidney.
2003,
Pubmed
,
Xenbase
Guerreiro,
The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish.
2007,
Pubmed
Guerreiro,
Piscine PTHrP regulation of calcium and phosphate transport in winter flounder renal proximal tubule primary cultures.
2010,
Pubmed
Guindon,
New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0.
2010,
Pubmed
Hoare,
Evaluating the ligand specificity of zebrafish parathyroid hormone (PTH) receptors: comparison of PTH, PTH-related protein, and tuberoinfundibular peptide of 39 residues.
2000,
Pubmed
Hori,
Minireview: fibroblast growth factor 23 in phosphate homeostasis and bone metabolism.
2011,
Pubmed
Hoshi,
Morphological characterization of skeletal cells in Cbfa1-deficient mice.
1999,
Pubmed
Huitema,
Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish.
2012,
Pubmed
Kalev-Zylinska,
Runx3 is required for hematopoietic development in zebrafish.
2003,
Pubmed
Kawakami,
Tol2: a versatile gene transfer vector in vertebrates.
2007,
Pubmed
,
Xenbase
Khanal,
Endocrine regulation of calcium transport in epithelia.
2008,
Pubmed
Kimmel,
Stages of embryonic development of the zebrafish.
1995,
Pubmed
,
Xenbase
Kronenberg,
Functional analysis of the PTH/PTHrP network of ligands and receptors.
1998,
Pubmed
Li,
Tracking gene expression during zebrafish osteoblast differentiation.
2009,
Pubmed
Lu,
FGF23 in skeletal modeling and remodeling.
2011,
Pubmed
Martin,
Regulation and function of the FGF23/klotho endocrine pathways.
2012,
Pubmed
Nishio,
Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene.
2006,
Pubmed
Okabe,
The origin of the parathyroid gland.
2004,
Pubmed
On,
Functional Pairing of Class B1 Ligand-GPCR in Cephalochordate Provides Evidence of the Origin of PTH and PACAP/Glucagon Receptor Family.
2015,
Pubmed
,
Xenbase
Pfaffl,
A new mathematical model for relative quantification in real-time RT-PCR.
2001,
Pubmed
Pinheiro,
Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken.
2010,
Pubmed
,
Xenbase
Potts,
Parathyroid hormone: past and present.
2005,
Pubmed
Putnam,
The amphioxus genome and the evolution of the chordate karyotype.
2008,
Pubmed
Quiros-Gonzalez,
Central genes, pathways and modules that regulate bone mass.
2014,
Pubmed
Radanovic,
Regulation of intestinal phosphate transport. I. Segmental expression and adaptation to low-P(i) diet of the type IIb Na(+)-P(i) cotransporter in mouse small intestine.
2005,
Pubmed
Robu,
p53 activation by knockdown technologies.
2007,
Pubmed
Rotllant,
Calcium mobilization from fish scales is mediated by parathyroid hormone related protein via the parathyroid hormone type 1 receptor.
2005,
Pubmed
Rotllant,
Ligand binding and signalling pathways of PTH receptors in sea bream (Sparus auratus) enterocytes.
2006,
Pubmed
Rotllant,
Sparc (Osteonectin) functions in morphogenesis of the pharyngeal skeleton and inner ear.
2008,
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
Saxena,
Sox10-dependent neural crest origin of olfactory microvillous neurons in zebrafish.
2013,
Pubmed
Suzuki,
Parathyroid hormone 1 (1-34) acts on the scales and involves calcium metabolism in goldfish.
2011,
Pubmed
Sánchez,
Characterization of the sea bass melanocortin 5 receptor: a putative role in hepatic lipid metabolism.
2009,
Pubmed
Sánchez,
Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax).
2009,
Pubmed
Tseng,
Effects of stanniocalcin 1 on calcium uptake in zebrafish (Danio rerio) embryo.
2009,
Pubmed
Wang,
Deletion mutagenesis of large (12-kb) plasmids by a one-step PCR protocol.
2001,
Pubmed
Witten,
A comparative view on mechanisms and functions of skeletal remodelling in teleost fish, with special emphasis on osteoclasts and their function.
2009,
Pubmed
Wolfe,
Robustness--it's not where you think it is.
2000,
Pubmed
Yadav,
Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification.
2011,
Pubmed
Yan,
Duplicated zebrafish co-orthologs of parathyroid hormone-related peptide (PTHrP, Pthlh) play different roles in craniofacial skeletogenesis.
2012,
Pubmed
Zheng,
Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo.
2003,
Pubmed
van der Velden,
The polycomb group protein ring1b/rnf2 is specifically required for craniofacial development.
2013,
Pubmed
