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

Suarez-Bregua, Paula and Torres-Nuñez, Eva and Saxena, Ankur and Guerreiro, Pedro and Braasch, Ingo and Prober, David A. and Moran, Paloma and Cerda-Reverter, Jose Miguel and Du, Shao Jun and Adrio, Fatima and Power, Deborah M. and Canario, Adelino V. M. and Postlethwait, John H. and Bronner, Marianne E. and Cañestro, Cristian and Rotllant, Josep (2016) Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway. FASEB Journal, 31 (2). pp. 569-583. ISSN 0892-6638. PMCID PMC5240660.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription Data CentralArticle
Saxena, Ankur0000-0001-8646-2887
Braasch, Ingo0000-0003-4766-611X
Prober, David A.0000-0002-7371-4675
Moran, Paloma0000-0002-3644-8507
Bronner, Marianne E.0000-0003-4274-1862
Additional Information:© 2017 FASEB. Received July 27, 2016. Accepted October 11, 2016. Published online before print October 24, 2016. The authors thank Yi-lin Yan (University of Oregon) for providing the tip39 (PTH2) expression vector; Prof. N. Lawson (University of Massachusetts Medical School, Worcester, MA, USA) and Prof. K. Kawakami (National Institute of Genetics, Mishima, Japan) for providing the iTol2 constructs; D.A.P. for the hcrt:tdTomato line and Prof. K. M. Kwan (University Of Utah, Salt Lake City, UT, USA) for the bactin2:H2A-mCherry line; Inés Pazos and Jesús Méndez [Scientific and Technological Research Assistance Centre (CACTI), University of Vigo] for their advice and assistance with the confocal microscope; Rub´en Chamorro and Rosa Ceinos (IIM–CSIC) for their help in handling and care of the fish and David Guede and José R. Caeiro (University of Santiago de Compostela, Santiago, Spain) for their advice and assistance with the micro-CT SkyScan. This work was funded by the Spanish Economy and Competitiveness Ministry Project ALG2011-23581 and AGL2014-52473R (to J.R.); the Portuguese Foundation for Science and Technology (Project PTDC/BIA-ANM/4225/2012-phos-fate; to P.G.); U. S. National Institutes of Health/Office of the Director Grant R01OD011116 (alias R01 RR020833; to J.H.P.); Generalitat de Catalunya (Grant SGR2014-290) and the Spanish Economy and Competitiveness Ministry (Project BFU2010-14875; to C.C.). Partial funding was obtained from Science and Innovation Ministry (AGL2010-22247-C03-01; to J.M.C.-R.), a Campus do Mar Ph.D. grant, and Xunta de Galicia (Santiago, Spain; Project AGL2014-52473R) (to P.S.B.). J. Rotllant and P. Suarez-Bregua conceived, designed, and coordinated the study; C. Cañestro, I. Braasch, and J. H. Postlethwait performed comparative genomics analyses; P. Suarez-Bregua and E. Torres-Nuñez performed promoter and mutation analysis; J. Rotllant performed transgenic lines creation and screening with support from P. Suarez-Bregua and E. Torres-Nuñez; J. Cerda-Reverter and P. Suarez-Bregua performed receptor binding studies; P. Suarez-Bregua, A. Saxena, and M. E. Bronner performed laser ablation studies; P. Moran, D. A. Prober, P. Guerreiro,D. M. Power, S. J.Du, F. Adrio, D. M. Power, and A. V. M. Canario provided technical support and contributed to methodology; and P. Suarez-Bregua, C. Cañestro, and J. Rotllant wrote and revised the manuscript with input from A. Saxena, J. H. Postlethwait, and M. E. Bronner.
Funding AgencyGrant Number
Ministerio de Economía y Competitividad (MINECO)ALG2011-23581
Ministerio de Economía y Competitividad (MINECO)AGL2014-52473R
Fundação para a Ciência e a Tecnologia (FCT)PTDC/BIA-ANM/4225/2012-phos-fate
NIHR01 RR020833
Generalitat de CatalunyaSGR2014-290
Ministerio de Economía y Competitividad (MINECO)BFU2010-14875
Ministerio de Economía y Competitividad (MINECO)AGL2010-22247- C03-01
Xunta de GaliciaAGL2014-52473R
Subject Keywords:runx • phosphate • calcium • hypothalamus • fgf23
Issue or Number:2
PubMed Central ID:PMC5240660
Record Number:CaltechAUTHORS:20170206-080130616
Persistent URL:
Official Citation:Paula Suarez-Bregua, Eva Torres-Nuñez, Ankur Saxena, Pedro Guerreiro, Ingo Braasch, David A. Prober, Paloma Moran, Jose Miguel Cerda-Reverter, Shao Jun Du, Fatima Adrio, Deborah M. Power, Adelino V. M. Canario, John H. Postlethwait, Marianne E. Bronner, Cristian Cañestro, and Josep Rotllant Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway FASEB J fj.201600815R; published ahead of print October 24, 2016, doi:10.1096/fj.201600815R
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74058
Deposited By: Ruth Sustaita
Deposited On:06 Feb 2017 20:25
Last Modified:03 Oct 2019 16:34

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