Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/11270 |
Resumo: | 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. |
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Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathwayBass Dicentrarchus-LabraxWhole-genome duplicationPhosphate homeostasisSkeletal mineralizationConserved syntenyTeleost fishZebrafishReceptorCalciumGeneRegulation 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.Spanish 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]Federation of American Society of Experimental BiologySapientiaSuarez-Bregua, PaulaTorres-Nunez, EvaSaxena, AnkurGuerreiro, PedroBraasch, IngoProber, David A.Moran, PalomaMiguel Cerda-Reverter, JoseDu, Shao JunAdrio, FatimaPower, Deborah M.Canario, Adelino V. M.Postlethwait, John H.Bronner, Marianne E.Canestro, CristianRotllant, Josep2018-12-07T14:52:56Z2017-022017-02-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/11270eng0892-663810.1096/fj.201600815Rinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:23:02Zoai:sapientia.ualg.pt:10400.1/11270Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:02:47.948275Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
title |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
spellingShingle |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway Suarez-Bregua, Paula Bass Dicentrarchus-Labrax Whole-genome duplication Phosphate homeostasis Skeletal mineralization Conserved synteny Teleost fish Zebrafish Receptor Calcium Gene |
title_short |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
title_full |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
title_fullStr |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
title_full_unstemmed |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
title_sort |
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway |
author |
Suarez-Bregua, Paula |
author_facet |
Suarez-Bregua, Paula Torres-Nunez, Eva Saxena, Ankur Guerreiro, Pedro Braasch, Ingo Prober, David A. Moran, Paloma Miguel Cerda-Reverter, Jose Du, Shao Jun Adrio, Fatima Power, Deborah M. Canario, Adelino V. M. Postlethwait, John H. Bronner, Marianne E. Canestro, Cristian Rotllant, Josep |
author_role |
author |
author2 |
Torres-Nunez, Eva Saxena, Ankur Guerreiro, Pedro Braasch, Ingo Prober, David A. Moran, Paloma Miguel Cerda-Reverter, Jose Du, Shao Jun Adrio, Fatima Power, Deborah M. Canario, Adelino V. M. Postlethwait, John H. Bronner, Marianne E. Canestro, Cristian Rotllant, Josep |
author2_role |
author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Suarez-Bregua, Paula Torres-Nunez, Eva Saxena, Ankur Guerreiro, Pedro Braasch, Ingo Prober, David A. Moran, Paloma Miguel Cerda-Reverter, Jose Du, Shao Jun Adrio, Fatima Power, Deborah M. Canario, Adelino V. M. Postlethwait, John H. Bronner, Marianne E. Canestro, Cristian Rotllant, Josep |
dc.subject.por.fl_str_mv |
Bass Dicentrarchus-Labrax Whole-genome duplication Phosphate homeostasis Skeletal mineralization Conserved synteny Teleost fish Zebrafish Receptor Calcium Gene |
topic |
Bass Dicentrarchus-Labrax Whole-genome duplication Phosphate homeostasis Skeletal mineralization Conserved synteny Teleost fish Zebrafish Receptor Calcium Gene |
description |
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. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-02 2017-02-01T00:00:00Z 2018-12-07T14:52:56Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/11270 |
url |
http://hdl.handle.net/10400.1/11270 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0892-6638 10.1096/fj.201600815R |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Federation of American Society of Experimental Biology |
publisher.none.fl_str_mv |
Federation of American Society of Experimental Biology |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133262412513280 |