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

2017-02Journal article Open access
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dc.contributor.authorSuarez-Bregua, Paula
dc.contributor.authorTorres-Nunez, Eva
dc.contributor.authorSaxena, Ankur
dc.contributor.authorGuerreiro, Pedro
dc.contributor.authorBraasch, Ingo
dc.contributor.authorProber, David A.
dc.contributor.authorMoran, Paloma
dc.contributor.authorMiguel Cerda-Reverter, Jose
dc.contributor.authorDu, Shao Jun
dc.contributor.authorAdrio, Fatima
dc.contributor.authorPower, Deborah M.
dc.contributor.authorCanario, Adelino V. M.
dc.contributor.authorPostlethwait, John H.
dc.contributor.authorBronner, Marianne E.
dc.contributor.authorCanestro, Cristian
dc.contributor.authorRotllant, Josep
dc.date.accessioned2018-12-07T14:52:56Z
dc.date.available2018-12-07T14:52:56Z
dc.date.issued2017-02
dc.description.abstractRegulation 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.
dc.description.sponsorshipSpanish Economy and Competitiveness Ministry Project [ALG2011-23581, AGL2014-52473R]; Portuguese Foundation for Science and Technology [PTDC/BIA-ANM/4225/2012-phos-fate]; U. S. National Institutes of Health/Office of the Director Grant [R01OD011116, R01 RR020833]; Generalitat de Catalunya [SGR2014-290]; Spanish Economy and Competitiveness Ministry [BFU2010-14875]; Science and Innovation Ministry [AGL2010-22247-C03-01]; Campus do Mar Ph.D. grant; Xunta de Galicia (Santiago, Spain) [AGL2014-52473R]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1096/fj.201600815R
dc.identifier.issn0892-6638
dc.identifier.issn1530-6860
dc.identifier.urihttp://hdl.handle.net/10400.1/11270
dc.language.isoeng
dc.peerreviewedyes
dc.publisherFederation of American Society of Experimental Biology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBass Dicentrarchus-Labrax
dc.subjectWhole-genome duplication
dc.subjectPhosphate homeostasis
dc.subjectSkeletal mineralization
dc.subjectConserved synteny
dc.subjectTeleost fish
dc.subjectZebrafish
dc.subjectReceptor
dc.subjectCalcium
dc.subjectGene
dc.titlePth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-ANM%2F4225%2F2012/PT
oaire.citation.endPage583
oaire.citation.issue2
oaire.citation.startPage569
oaire.citation.titleFASEB Journal
oaire.citation.volume31
oaire.fundingStream3599-PPCDT
person.familyNameGuerreiro da Costa Guerreiro
person.familyNamePower
person.familyNameCanario
person.givenNamePedro Miguel
person.givenNameDeborah Mary
person.givenNameAdelino
person.identifierA-2539-2009
person.identifier143624
person.identifier.ciencia-id5C13-965D-3148
person.identifier.ciencia-id891A-8A44-3CAE
person.identifier.ciencia-id1F1E-D3B3-F804
person.identifier.orcid0000-0001-5371-7919
person.identifier.orcid0000-0003-1366-0246
person.identifier.orcid0000-0002-6244-6468
person.identifier.ridC-7942-2009
person.identifier.scopus-author-id7101806760
person.identifier.scopus-author-id56568523700
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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