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dc.contributor.authorPetratou, Kleio
dc.contributor.authorSubkhankulova, Tatiana
dc.contributor.authorLister, James A
dc.contributor.authorRocco, Andrea
dc.contributor.authorSchwetlick, Hartmut
dc.contributor.authorKelsh, Robert N
dc.date.accessioned2018-12-14T00:31:47Z
dc.date.available2018-12-14T00:31:47Z
dc.date.issued2018-10
dc.identifier.issn1553-7390
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286933
dc.description.abstractMultipotent neural crest (NC) progenitors generate an astonishing array of derivatives, including neuronal, skeletal components and pigment cells (chromatophores), but the molecular mechanisms allowing balanced selection of each fate remain unknown. In zebrafish, melanocytes, iridophores and xanthophores, the three chromatophore lineages, are thought to share progenitors and so lend themselves to investigating the complex gene regulatory networks (GRNs) underlying fate segregation of NC progenitors. Although the core GRN governing melanocyte specification has been previously established, those guiding iridophore and xanthophore development remain elusive. Here we focus on the iridophore GRN, where mutant phenotypes identify the transcription factors Sox10, Tfec and Mitfa and the receptor tyrosine kinase, Ltk, as key players. Here we present expression data, as well as loss and gain of function results, guiding the derivation of an initial iridophore specification GRN. Moreover, we use an iterative process of mathematical modelling, supplemented with a Monte Carlo screening algorithm suited to the qualitative nature of the experimental data, to allow for rigorous predictive exploration of the GRN dynamics. Predictions were experimentally evaluated and testable hypotheses were derived to construct an improved version of the GRN, which we showed produced outputs consistent with experimentally observed gene expression dynamics. Our study reveals multiple important regulatory features, notably a sox10-dependent positive feedback loop between tfec and ltk driving iridophore specification; the molecular basis of sox10 maintenance throughout iridophore development; and the cooperation between sox10 and tfec in driving expression of pnp4a, a key differentiation gene. We also assess a candidate repressor of mitfa, a melanocyte-specific target of sox10. Surprisingly, our data challenge the reported role of Foxd3, an established mitfa repressor, in iridophore regulation. Our study builds upon our previous systems biology approach, by incorporating physiologically-relevant parameter values and rigorous evaluation of parameter values within a qualitative data framework, to establish for the first time the core GRN guiding specification of the iridophore lineage.
dc.format.mediumElectronic-eCollection
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectChromatophores
dc.subjectStem Cells
dc.subjectEmbryo, Nonmammalian
dc.subjectNeural Crest
dc.subjectAnimals
dc.subjectAnimals, Genetically Modified
dc.subjectZebrafish
dc.subjectZebrafish Proteins
dc.subjectSystems Biology
dc.subjectGene Expression Regulation, Developmental
dc.subjectCell Lineage
dc.subjectMutation
dc.subjectForkhead Transcription Factors
dc.subjectGene Regulatory Networks
dc.subjectSOXE Transcription Factors
dc.titleA systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest.
dc.typeArticle
prism.issueIdentifier10
prism.publicationDate2018
prism.publicationNamePLoS Genet
prism.startingPagee1007402
prism.volume14
dc.identifier.doi10.17863/CAM.34242
dcterms.dateAccepted2018-08-22
rioxxterms.versionofrecord10.1371/journal.pgen.1007402
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10-04
dc.contributor.orcidLister, James A [0000-0002-8505-6710]
dc.contributor.orcidRocco, Andrea [0000-0002-0974-5522]
dc.contributor.orcidKelsh, Robert N [0000-0002-9381-0066]
dc.identifier.eissn1553-7404
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-10-04


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