Thedifferentiationofmusclecellsistranscriptionallyregulated,inpartbythemyocyteenhancerfactor-2,MEF2.DuringmyogenesisMEF2bindstoMyoDandotherbasichelix-loop-helixfactorstoactivatetranscriptionofgenesinvolvedinmusclecelldifferentiation.TranscriptionalactivationbyMEF2isblockedbyinteractionwithHDAC5andotherhistonedeacetylases.Inundifferentiatedmyoblasts,HDAC5ispresentinthenucleuswhereitbindstoMEF2toblockactivationofmusclegenes.WhenactivatedbyIGF-1signaling,CaMkinasephosphorylatesHDACproteins,causingthemtobeexportedfromthenucleus,releasingtheblockonMEF2transcriptionalactivationandallowingdifferentiationtoproceed.TranscriptioncofactorsalsointeractwithMEF2tocontributetogeneregulationandmyogenesis.ThetranscriptionalregulatorNFAT,forexample,actsasacofactorforMEF2whencalciumandcalcineurinsignalingactivateit.TherearefourmembersoftheMef2genefamily,Mef2a-2d.Mef2aisexpressedinbrain,heartandskeletalmuscle.Mef2cisinvolvedinmyogenesisincardiacandskeletalmuscle.Mef2diswidelyexpressed,andmaybeinvolvedintheregulationofTcellfunctionaswellasmuscle.(SeeMef2Pathway)SeveralfactorsregulateMef2transcriptionfactors,includingMapkinasesandhistonedeacetylase(HDAC)enzymes.Mef2isphosphorylatedbyp38mapkinase,andphosphorylationofMef2cbyp38contributestoskeletalmuscledifferentiation.BMK-1(alsocalledErk5)isanothermemberoftheMapkinasefamilythatregulatestheactivityofMef2familymembersandisuniqueinthatitappearsitselftopossessatranscriptionalactivationdomainandactasatranscriptionalcoactivator.Mekk3disruptionpreventednormalcardiovasculardevelopmentinmiceandappearstosignalthroughp38andMef2cinnormalcardiovasculardevelopment.

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