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Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate.

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dc.contributor.authorThambyrajah, Roshana
dc.contributor.authorMaqueda, Maria
dc.contributor.authorNeo, Wen Hao
dc.contributor.authorImbach, Kathleen
dc.contributor.authorGuillén, Yolanda
dc.contributor.authorGrases, Daniela
dc.contributor.authorFadlullah, Zaki
dc.contributor.authorGambera, Stefano
dc.contributor.authorMatteini, Francesca
dc.contributor.authorWang, Xiaonan
dc.contributor.authorCalero-Nieto, Fernando J
dc.contributor.authorEsteller, Manel
dc.contributor.authorFlorian, Maria Carolina
dc.contributor.authorPorta, Eduard
dc.contributor.authorBenedito, Rui
dc.contributor.authorGöttgens, Berthold
dc.contributor.authorLacaud, Georges
dc.contributor.authorEspinosa, Lluis
dc.contributor.authorBigas, Anna
dc.contributor.funderAgencia Estatal de Investigación (España)es_ES
dc.contributor.funderCancer Research UK (Reino Unido)es_ES
dc.contributor.funderMinisterio de Ciencia e Innovación (España)es_ES
dc.date.accessioned2024-07-09T10:13:19Z
dc.date.available2024-07-09T10:13:19Z
dc.date.issued2024-02-21
dc.description.abstractHematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe thank Sarah Bray and David Sprinzak for critical discussions about cis interactions. We thank Genentech for kindly gifting the anti-JAG1 and anti-NOTCH1 antibodies. We thank all members of Espinosa and Bigas laboratories for helpful discussions and technical support. All illustrations in the manuscript were created with BioRender.com. We also thank the animal facility, FACS facility, and genomic facility of the PRBB and CRUK Manchester Institute for their technical support. This work was funded by grants from SAF2016-75613-R and PID2019-104695RB-I00 from Agencia Estatal de Investigación (AEI) and SLT002/16/00299 from Department of Health, Generalitat de Cataluña and 2021 SGR 00039 from AGAUR, Generalitat de Catalunya. The work in the G.L. laboratory is supported by Blood Cancer UK (19014) and Cancer Research UK Manchester Institute Core Grant (C5759/A27412). The work in R.B. laboratory was supported by a grant from the Ministerio de Ciencia e Innovación (MCIN - PID2020-120252RB-I00). RT is a recipient of BP2016 (00021) and BP/MSCA 2018 (00034) fellowship programs from Generalitat de Catalunya/MSCA. E.P. is a recipient of RYC2019-026415-I. M.M. is a recipient of a grant from the Instituto Carlos III, grant number CA22/00011 (cofunded by the European Social Fund Plus, ESF+, and by the European Union).es_ES
dc.format.number1es_ES
dc.format.page1604es_ES
dc.format.volume15es_ES
dc.identifier.citationNat Commun. 2024 Feb 21;15(1):1604.es_ES
dc.identifier.doi10.1038/s41467-024-45716-yes_ES
dc.identifier.e-issn2041-1723es_ES
dc.identifier.journalNature communicationses_ES
dc.identifier.pubmedID38383534es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/20320
dc.language.isoenges_ES
dc.publisherNature Publishing Groupes_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/SAF2016-75613-Res_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/PID2019-104695RB-I00es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/SLT002/16/00299es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/MCIN/PID2020-120252RB-I00es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/RYC2019-026415-Ies_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/CA22/00011es_ES
dc.relation.publisherversion10.1038/s41467-024-45716-yes_ES
dc.repisalud.institucionCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Genética Molecular de la Angiogénesises_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshReceptor, Notch1es_ES
dc.subject.meshHematopoietic Stem Cellses_ES
dc.subject.meshCell Differentiationes_ES
dc.subject.meshAortaes_ES
dc.subject.meshArterieses_ES
dc.subject.meshMesonephroses_ES
dc.subject.meshGonadses_ES
dc.titleCis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate.es_ES
dc.typejournal articlees_ES
dc.type.hasVersionVoRes_ES
dspace.entity.typePublication
relation.isAuthorOfPublication02d9828d-ff71-41ad-8448-60d280555a9e
relation.isAuthorOfPublication924c4677-29f1-4917-92d2-765d534c2242
relation.isAuthorOfPublication.latestForDiscovery02d9828d-ff71-41ad-8448-60d280555a9e

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