Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.
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.
Institute of Marine Research, Spanish National Research Council (IIM-CSIC), Vigo, Spain.
Paula
P
Suarez-Bregua
Institute of Marine Research, Spanish National Research Council (IIM-CSIC), Vigo, Spain.
Eva
E
Torres-Nuñez
California Institute of Technology, Pasadena, California, USA.|Department of Biological Sciences, University of Illinois, Chicago, Illinois, USA.
Ankur
A
Saxena
Center of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
Pedro
P
Guerreiro
Institute of Neuroscience, University of Oregon, Eugene, Oregon, USA.
Ingo
I
Braasch
California Institute of Technology, Pasadena, California, USA.
David A
DA
Prober
Department of Biochemistry, Genetics, and Immunology, University of Vigo, Vigo, Spain.
Paloma
P
Moran
Institute of Aquaculture Torre de La Sal (IATS-CSIC), Castellón, Spain.
Jose Miguel
JM
Cerda-Reverter
Department of Molecular and Cellular Biology, University of Maryland, Baltimore, Maryland, USA.
Shao Jun
SJ
Du
Department of Cell Biology, University of Santiago de Compostela, Santiago de Compostela Spain; and.
Fatima
F
Adrio
Center of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
Deborah M
DM
Power
Center of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.
Adelino V M
AV
Canario
Institute of Neuroscience, University of Oregon, Eugene, Oregon, USA.
John H
JH
Postlethwait
California Institute of Technology, Pasadena, California, USA.
Marianne E
ME
Bronner
Department de Genètica, Microbiologia i Estadística, Institut de Recerca de la Biodiversitat (IRBio), Universitat de Barcelona, Barcelona, Spain.
Cristian
C
Cañestro
Institute of Marine Research, Spanish National Research Council (IIM-CSIC), Vigo, Spain; rotllant@iim.csic.es.
Josep
J
Rotllant
D000818:Animals; D030801:Animals, Genetically Modified; D005075:Biological Evolution; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D003001:Cloning, Molecular; D000089703:Fibroblast Growth Factor-23; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D023281:Genomics; D007814:Larva; D008322:Mammals; D009415:Nerve Net; D009474:Neurons / Q000378:metabolism; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D026801:Synteny; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology
C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; C000622181:Pth4 protein, zebrafish; D029867:Xenopus Proteins; D000089703:Fibroblast Growth Factor-23
calcium; fgf23; hypothalamus; phosphate; runx