An Iterative Genetic and Dynamical Modelling Approach Identifies Novel Features of the Gene Regulatory Network Underlying Melanocyte Development 英文参考文献.docVIP

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An Iterative Genetic and Dynamical Modelling Approach Identifies Novel Features of the Gene Regulatory Network Underlying Melanocyte Development 英文参考文献.doc

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An Iterative Genetic and Dynamical Modelling Approach Identifies Novel Features of the Gene Regulatory Network Underlying Melanocyte Development 英文参考文献

AnIterativeGeneticandDynamicalModellingApproach IdentifiesNovelFeaturesoftheGeneRegulatory NetworkUnderlyingMelanocyteDevelopment EmmaR.Greenhill1,AndreaRocco2¤a,LauraVibert1,MasatakaNikaido1¤b,RobertN.Kelsh1* 1DepartmentofBiologyandBiochemistryandCentreforRegenerativeMedicine,UniversityofBath,Bath,UnitedKingdom,2DepartmentofMathematics,Universityof Bath,Bath,UnitedKingdom Abstract Themechanismsgeneratingstablydifferentiatedcell-typesfrommultipotentprecursorsarekeytounderstandingnormal developmentandhaveimplicationsfortreatmentofcancerandthetherapeuticuseofstemcells.Pigmentcellsareamajor derivativeofneuralcreststemcellsandakeymodelcell-typeforourunderstandingofthegeneticsofcelldifferentiation. Several factors driving melanocyte fate specification have been identified, including the transcription factor and master regulatorofmelanocytedevelopment,Mitf,andWntsignallingandthemultipotencyandfatespecificationfactor,Sox10, which drive mitf expression. While these factors together drive multipotent neural crest cells to become specified melanoblasts,themechanismsstabilisingmelanocytedifferentiationremainunclear.Furthermore,thereiscontroversyover whether Sox10 has an ongoing role in melanocyte differentiation. Here we use zebrafish to explore in vivo the gene regulatory network (GRN) underlying melanocyte specification and differentiation. We use an iterative process of mathematicalmodellingandexperimentalobservationtoexploremethodicallythecoremelanocyteGRNwehavedefined. WeshowthatSox10isnotrequiredforongoingdifferentiationandexpressionisdownregulatedindifferentiatingcells,in response to Mitfa and Hdac1. Unexpectedly, we find that Sox10 represses Mitf-dependent expression of melanocyte differentiationgenes.OursystemsbiologyapproachallowedustopredicttwonovelfeaturesofthemelanocyteGRN,which we then validate experimentally. Specifically, we show that maintenance of mitfa expression is Mitfa-dependent, and identify Sox9b as providing an Mitfa-independent input to melanocyte d