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dc.contributor.authorAzzarelli, Robertaen
dc.contributor.authorHurley, Cen
dc.contributor.authorSznurkowska, Magdalenaen
dc.contributor.authorRulands, Steffenen
dc.contributor.authorHardwick, Lauraen
dc.contributor.authorGamper, Ien
dc.contributor.authorTahseen Ali, Fahaden
dc.contributor.authorMcCracken, Len
dc.contributor.authorHindley, Cen
dc.contributor.authorMcDuff, Fen
dc.contributor.authorShaw, Soniaen
dc.contributor.authorKemp, Richarden
dc.contributor.authorJones, Ken
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorHuch Ortega, Meritxellen
dc.contributor.authorEvan, Gerarden
dc.contributor.authorSimons, Benjaminen
dc.contributor.authorWinton, Douglasen
dc.contributor.authorPhilpott, Annaen
dc.date.accessioned2017-07-17T09:44:03Z
dc.date.available2017-07-17T09:44:03Z
dc.date.issued2017-05-08en
dc.identifier.issn1534-5807
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/265388
dc.description.abstractThe proneural transcription factor Neurogenin3 (Ngn3) plays a critical role in pancreatic endocrine cell differentiation, although regulation of Ngn3 protein is largely unexplored. Here we demonstrate that Ngn3 protein undergoes cyclin-dependent kinase (Cdk)-mediated phosphorylation on multiple serine-proline sites. Replacing wild-type protein with a phosphomutant form of Ngn3 increases α cell generation, the earliest endocrine cell type to be formed in the developing pancreas. Moreover, un(der)phosphorylated Ngn3 maintains insulin expression in adult β cells in the presence of elevated c-Myc and enhances endocrine specification during ductal reprogramming. Mechanistically, preventing multi-site phosphorylation enhances both Ngn3 stability and DNA binding, promoting the increased expression of target genes that drive differentiation. Therefore, multi-site phosphorylation of Ngn3 controls its ability to promote pancreatic endocrine differentiation and to maintain β cell function in the presence of pro-proliferation cues and could be manipulated to promote and maintain endocrine differentiation in vitro and in vivo.
dc.description.sponsorshipThis work was supported by the MRC Research GrantMR/K018329/1; the Rosetrees Trust (to A.P. and R.A.); the MRC Research Grant MR/L021129/1 and core support from the Wellcome Trust and the MRC Cambridge Stem Cell Institute (to A.P. and F.A.); the MRC Doctoral Training Awards (to L.M., L.H., and M.S.); the CRUK studentship (to C. Hurley); the Wellcome Trust 098357/Z/12/Z (to B.D.S. and R.A.); and the Wellcome Trust 097922/Z/11/Z and the Clinical Research Infrastructure Single-Cell Facility (MR/M008975/1) (to B.G.). D.W. and R.K. are CRUK funded; G.E. is CRUK A12077 funded. M.H. is a Sir Henry Dale fellow and is supported by the Wellcome Trust 104151/Z/14/A and the Royal Society.
dc.languageengen
dc.language.isoenen
dc.publisherElsevier (Cell Press)
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectdiabetesen
dc.subjectendocrine differentiationen
dc.subjectinsulinomaen
dc.subjectneurogenin3en
dc.subjectpancreatic developmenten
dc.subjectpancreatic organoidsen
dc.subjectproneural bHLH transcription factorsen
dc.subjectβ cellsen
dc.titleMulti-site Neurogenin3 Phosphorylation Controls Pancreatic Endocrine Differentiationen
dc.typeArticle
prism.endingPage286.e5
prism.issueIdentifier3en
prism.publicationDate2017en
prism.publicationNameDevelopmental Cellen
prism.startingPage274
prism.volume41en
dc.identifier.doi10.17863/CAM.11560
dcterms.dateAccepted2017-04-04en
rioxxterms.versionofrecord10.1016/j.devcel.2017.04.004en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-05-08en
dc.contributor.orcidRulands, Steffen [0000-0001-6398-1553]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidHuch Ortega, Meritxell [0000-0002-1545-5265]
dc.contributor.orcidEvan, Gerard [0000-0003-0412-1216]
dc.contributor.orcidSimons, Benjamin [0000-0002-3875-7071]
dc.contributor.orcidPhilpott, Anna [0000-0003-3789-2463]
dc.identifier.eissn1878-1551
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/K018329/1)
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idMRC (MR/K50127X/1)
pubs.funder-project-idCancer Research UK (C14303_do not transfer)
pubs.funder-project-idCancer Research UK (CB4230)
pubs.funder-project-idWELLCOME TRUST (103805/Z/14/Z)
pubs.funder-project-idMRC (MR/L021129/1)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idWellcome Trust (097922/Z/11/Z)
pubs.funder-project-idWELLCOME TRUST (098357/Z/12/Z)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M008975/1)
cam.issuedOnline2017-04-27en
cam.orpheus.successThu Jan 30 12:53:32 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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