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Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

2019Journal article Open access
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dc.contributor.authorSantos, João
dc.contributor.authorMendes-Silva, Leonardo
dc.contributor.authorAfonso,Vanessa
dc.contributor.authorMartins, Gil
dc.contributor.authorMachado, Rui
dc.contributor.authorLopes, Joao
dc.contributor.authorCancela, M. Leonor
dc.contributor.authorFutschik, Matthias
dc.contributor.authorSachinidis, Agapios
dc.contributor.authorGavaia, Paulo
dc.contributor.authorBragança, José
dc.date.accessioned2019-09-03T12:34:06Z
dc.date.available2019-09-03T12:34:06Z
dc.date.issued2019
dc.description.abstractMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.pt_PT
dc.description.sponsorshipAgência financiadora: Fundação para a Ciência e a Tecnologia (FCT) Comissão de Coordenação e Desenvolvimento Regional do Algarve (CCDR Algarve) ALG-01-0145-FEDER-28044; DFG 568/17-2 Algarve Biomedical Center (ABC) Municipio de Loulépt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1038/s41419-019-1816-6
dc.identifier.issn2041-4889
dc.identifier.urihttp://hdl.handle.net/10400.1/12749
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Publishing Grouppt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleExogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphantspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F04773%2F2013/PT
oaire.citation.issue8pt_PT
oaire.citation.startPage582pt_PT
oaire.citation.titleCell Death and Diseasept_PT
oaire.citation.volume10pt_PT
oaire.fundingStream5876
person.familyNameSantos
person.familyNameMendes e Silva
person.familyNameMartins
person.familyNameMachado
person.familyNameLopes
person.familyNameCancela
person.familyNameFutschik
person.familyNameGavaia
person.familyNameBragança
person.givenNameJoão
person.givenNameLeonardo
person.givenNameGil
person.givenNameRui
person.givenNameJoao
person.givenNameM. Leonor
person.givenNameMatthias
person.givenNamePaulo
person.givenNameJosé
person.identifier2373709
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person.identifier.ciencia-idA71B-AD01-3501
person.identifier.ciencia-idB619-FC16-D007
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person.identifier.orcid0000-0003-3114-6662
person.identifier.orcid0000-0002-6245-8071
person.identifier.orcid0000-0002-9582-1957
person.identifier.orcid0000-0001-9566-400X
person.identifier.ridK-8962-2018
person.identifier.ridA-6470-2011
person.identifier.scopus-author-id57201364200
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person.identifier.scopus-author-id6507104377
person.identifier.scopus-author-id6602220001
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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