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iRAGu: A Novel Inducible and Reversible Mouse Model for Ubiquitous Recombinase Activity

2017-11-10Journal article Open access
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dc.contributor.authorBonnet, Marie
dc.contributor.authorSarmento, Leonor Morais
dc.contributor.authorMartins, Ana C.
dc.contributor.authorSobral, Daniel
dc.contributor.authorSilva, Joana
dc.contributor.authorDemengeot, Jocelyne
dc.date.accessioned2017-11-23T19:31:40Z
dc.date.available2017-11-23T19:31:40Z
dc.date.issued2017-11-10
dc.descriptionThis deposit is composed by the main article plus the supplementary materials of the publication.pt_PT
dc.description.abstractDeveloping lymphocytes express the recombination activating genes (RAGs) 1 and 2 products that form a site specific recombinase complex (RAG), introducing double strand DNA breaks (DSBs) at recombination signal sequences (RSSs) flanking the V, D, and J gene segments in the antigen receptor loci. The subsequent steps in the reaction consist in the ligation of DSBs by ubiquitous enzymes of the non-homologous end joining DNA repair pathway. This mutagenesis process is responsible for the generation of the very large clonal diversity of T and B lymphocytes, itself allowing the recognition of a virtually open-ended antigenic universe. Sequences resembling RSS are found at high frequency all over the genome, and involved in RAG mediated illegitimate recombination and translocations. Hence, natural and induced ectopic activity of RAG is a threat to the genome only recently underscored. Here, we report and characterize a novel mouse transgenic system for which ubiquitous expression of the recombinase is inducible. In this system, the RAG1 protein is constitutively expressed and functional, while the RAG2 protein, coupled to the estrogen receptor, becomes functionally active upon 4-hydroxytamoxifen (TAM) administration. We describe two transgenic lines. The first one, when introgressed into an endogenous Rag2−/− genetic background is faithfully recapitulating lymphocyte development, repertoire dynamics and cryptic rearrangements, in a TAM-dependent manner. In this model, deprivation of TAM is followed by lymphocyte development arrest, evidencing the reversibility of the system. The second transgenic line is leaky, as the transgenes promote lymphocyte differentiation in absence of TAM treatment. Upon TAM-induction defects in lymphocytes composition and global health reveals the deleterious effect of uncontrolled RAG activity. Overall, this novel transgenic model provides a tool where RAG activity can be specifically manipulated to assess the dynamics of lymphocyte differentiation and the challenges imposed by the recombinase on the vertebrate genome.pt_PT
dc.description.sponsorshipFundação para a Ciência e a Tecnologia grants: (PTDC/BIA-GEN/116830/2010, fellowships); Portuguese League Against Cancer; Terry Fox Foundation.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBonnet M, Sarmento LM, Martins AC, Sobral D, Silva J and Demengeot J (2017) iRAGu: A Novel Inducible and Reversible Mouse Model for Ubiquitous Recombinase Activity. Front. Immunol. 8:1525. doi: 10.3389/fimmu.2017.01525pt_PT
dc.identifier.doi10.3389/fimmu.2017.01525pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.7/813
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Mediapt_PT
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fimmu.2017.01525/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectrecombination activating genept_PT
dc.subjecttransgenic mouse modelpt_PT
dc.subject4-hydroxytamoxifen inductionpt_PT
dc.subjectestrogen receptorpt_PT
dc.subjectlymphocyte developmentpt_PT
dc.subjectV(D)J recombinationpt_PT
dc.titleiRAGu: A Novel Inducible and Reversible Mouse Model for Ubiquitous Recombinase Activitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-GEN%2F116830%2F2010/PT
oaire.citation.endPage13pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleFrontiers in Immunologypt_PT
oaire.citation.volume8pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication210a45bb-0e47-4205-913a-112af5d6ea85
relation.isProjectOfPublication.latestForDiscovery210a45bb-0e47-4205-913a-112af5d6ea85

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