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dc.contributor.authorYiangou, Loukiaen
dc.contributor.authorGrandy, Rodrigo Aen
dc.contributor.authorOsnato, Annaen
dc.contributor.authorOrtmann, Danielen
dc.contributor.authorSinha, Sanjayen
dc.contributor.authorVallier, Ludovicen
dc.date.accessioned2019-09-25T23:30:19Z
dc.date.available2019-09-25T23:30:19Z
dc.date.issued2019-11en
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297106
dc.description.abstractThe mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys, and the cardiovascular system originate. Understanding the mechanisms that control mesoderm specification could inform many applications, including the development of regenerative medicine therapies to manage diseases affecting these tissues. Here, we used human pluripotent stem cells (hPSCs) to investigate the role of cell cycle in mesoderm formation. To this end, using small molecules or conditional gene knockdown, we inhibited proteins controlling G1 and G2/M cell cycle phases during the differentiation of hPSCs into lateral plate, cardiac, and presomitic mesoderm. These loss-of-function experiments revealed that regulators of the G1 phase such as cyclin-dependent kinases (CDKs) and phosphorylation of retinoblastoma protein (pRb) are necessary for efficient mesoderm formation in a context-dependent manner. Further investigations disclosed that inhibition of the G2/M regulator CDK1 decreases bone morphogenetic protein (BMP) signaling activity specifically during lateral plate mesoderm formation while reducing fibroblast growth factor (FGF)/extracellular signaling-regulated kinase 1/2 (ERK1/2) activity in all mesoderm subtypes. Taken together, our findings reveal that cell cycle regulators direct mesoderm formation by controlling the activity of key developmental pathways.
dc.description.sponsorshipThis work was supported by the Wellcome Trust PhD program (PSAG/048 to L.Y.); the European Research Council advanced grant New-Chol (ERC: 741707 to L.V. and R.A.G), a BHF Senior Research Fellowship (FS/13/29/30024 to S.S.), a core support grant from the Wellcome and Medical Research Council to the Wellcome – Medical Research Council Cambridge Stem Cell Institute (PSAG028) and a core support grant from the Wellcome to the Wellcome Sanger Institute (WT206194).
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectMesodermen
dc.subjectHumansen
dc.subjectUbiquitin-Protein Ligasesen
dc.subjectCyclin-Dependent Kinasesen
dc.subjectProtein Kinase Inhibitorsen
dc.subjectCell Cycleen
dc.subjectCell Differentiationen
dc.subjectMAP Kinase Signaling Systemen
dc.subjectCell Lineageen
dc.subjectRetinoblastoma Binding Proteinsen
dc.subjectHuman Embryonic Stem Cellsen
dc.titleCell cycle regulators control mesoderm specification in human pluripotent stem cells.en
dc.typeArticle
prism.endingPage17914
prism.issueIdentifier47en
prism.publicationDate2019en
prism.publicationNameThe Journal of biological chemistryen
prism.startingPage17903
prism.volume294en
dc.identifier.doi10.17863/CAM.44159
dcterms.dateAccepted2019-09-12en
rioxxterms.versionofrecord10.1074/jbc.ra119.008251en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-11en
dc.contributor.orcidYiangou, Loukia [0000-0003-1477-005X]
dc.contributor.orcidOsnato, Anna [0000-0001-5241-1512]
dc.contributor.orcidSinha, Sanjay [0000-0001-5900-1209]
dc.contributor.orcidVallier, Ludovic [0000-0002-3848-2602]
dc.identifier.eissn1083-351X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) ERC (741707)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Societal Challenges (668294-2 INTENS)
pubs.funder-project-idBritish Heart Foundation (FS/13/29/30024)
pubs.funder-project-idBritish Heart Foundation (FS/13/65/30441)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMRC (G0701448)
cam.orpheus.successThu Jan 30 10:38:04 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2019-11-30


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