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dc.contributor.authorTomic, Goran
dc.contributor.authorMorrissey, Edward
dc.contributor.authorKozar, Sarah
dc.contributor.authorBen-Moshe, Shani
dc.contributor.authorHoyle, Alice
dc.contributor.authorAzzarelli, Roberta
dc.contributor.authorKemp, Richard
dc.contributor.authorChilamakuri, Chandra Sekhar Reddy
dc.contributor.authorItzkovitz, Shalev
dc.contributor.authorPhilpott, Anna
dc.contributor.authorWinton, Douglas J
dc.date.accessioned2018-11-01T14:03:32Z
dc.date.available2018-11-01T14:03:32Z
dc.date.issued2018-09-06
dc.identifier.issn1934-5909
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284521
dc.description.abstractThe intestinal epithelium is largely maintained by self-renewing stem cells but with apparently committed progenitors also contributing, particularly following tissue damage. However, the mechanism of, and requirement for, progenitor plasticity in mediating pathological response remain unknown. Here we show that phosphorylation of the transcription factor Atoh1 is required for both the contribution of secretory progenitors to the stem cell pool and for a robust regenerative response. As confirmed by lineage tracing, Atoh1+ cells (Atoh1(WT)CreERT2 mice) give rise to multilineage intestinal clones both in the steady state and after tissue damage. In a phosphomutant Atoh1(9S/T-A)CreERT2 line, preventing phosphorylation of ATOH1 protein acts to promote secretory differentiation and inhibit the contribution of progenitors to self-renewal. Following chemical colitis, Atoh1+ cells of Atoh1(9S/T-A)CreERT2 mice have reduced clonogenicity that affects overall regeneration. Progenitor plasticity maintains robust self-renewal in the intestinal epithelium, and the balance between stem and progenitor fate is directly coordinated by ATOH1 multisite phosphorylation.
dc.description.sponsorshipCancer Research UK Welcome Trust Rosetrees Trust Stoneygate Trust
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectIntestinal Mucosa
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectRegeneration
dc.subjectCell Differentiation
dc.subjectPhosphorylation
dc.subjectFemale
dc.subjectMale
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.titlePhospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.
dc.typeArticle
prism.endingPage443.e7
prism.issueIdentifier3
prism.publicationDate2018
prism.publicationNameCell Stem Cell
prism.startingPage436
prism.volume23
dc.identifier.doi10.17863/CAM.31896
dcterms.dateAccepted2018-07-06
rioxxterms.versionofrecord10.1016/j.stem.2018.07.002
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidPhilpott, Anna [0000-0003-3789-2463]
dc.contributor.orcidWinton, Douglas [0000-0001-6067-7927]
dc.identifier.eissn1875-9777
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (CB4230)
pubs.funder-project-idWellcome Trust (103805/Z/14/Z)
pubs.funder-project-idRosetrees Trust (A790)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MR/K018329/1)
pubs.funder-project-idMedical Research Council (MR/L021129/1)
cam.issuedOnline2018-08-09


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International