PUBLICATION

Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway

Authors
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., Postlethwait, J.H., Bronner, M.E., Cañestro, C., Rotllant, J.
ID
ZDB-PUB-170204-7
Date
2017
Source
FASEB journal : official publication of the Federation of American Societies for Experimental Biology   31: 569-583 (Journal)
Registered Authors
Braasch, Ingo, Bronner-Fraser, Marianne, Cañestro-García, Cristian, Du, Shao Jun (Jim), Postlethwait, John H., Prober, David, Rotllant, Josep, Saxena, Ankur
Keywords
calcium, fgf23, hypothalamus, phosphate, runx
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Biological Evolution*
  • Bone Density
  • Bone and Bones/metabolism*
  • Brain/metabolism*
  • Cloning, Molecular
  • Gene Expression Regulation, Developmental/physiology*
  • Genomics
  • Larva
  • Mammals
  • Nerve Net
  • Neurons/metabolism
  • Parathyroid Hormone/genetics
  • Parathyroid Hormone/metabolism*
  • Parathyroid Hormone-Related Protein/genetics
  • Parathyroid Hormone-Related Protein/metabolism*
  • Signal Transduction/physiology*
  • Synteny
  • Xenopus Proteins/genetics
  • Xenopus Proteins/metabolism*
  • Zebrafish/embryology
PubMed
28148780 Full text @ FASEB J.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes