From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm 英文参考文献.docVIP
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From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm 英文参考文献
FromDynamicExpressionPatternstoBoundary
FormationinthePresomiticMesoderm
HendrikB.Tiedemann1,ElidaSchneltzer1,StefanZeiser2,BastianHoesel1,JohannesBeckers1,3,
GerhardK.H.Przemeck1,MartinHrabeˇ deAngelis1,3*
1InstituteofExperimentalGenetics,HelmholtzZentrumMu¨nchen-GermanResearchCenterforEnvironmentalHealth, Neuherberg,Germany,2KinesisPharmaBV,NK
Breda,TheNetherlands,3TechnischeUniversitaetMuenchen,CenterofLifeandFoodSciencesWeihenstephan,ChairofExperimentalGenetics,Freising,Germany
Abstract
Thesegmentationofthevertebratebodyislaiddownduringearlyembryogenesis.Theformationofsignalinggradients,
theperiodicexpressionofgenesoftheNotch-,Fgf-andWnt-pathwaysandtheirinterplayintheunsegmentedpresomitic
mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into
epithelializedstructures,thesomites.Althoughmanyinsilicomodelsdescribingpartialaspectsofsomitogenesisalready
exist,simulationsofacompletecausalchainfromgeneexpressioninthegrowthzoneviatheinteractionofmultiplecellsto
segmentationarerare.Here,wepresentanenhancedgeneregulatorynetwork(GRN)formiceinasimulationprogramthat
models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene
expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we
postulateanegativefeedbackofHES7onDll1leadingtoanoscillatingDll1expressionasseeninvivo.Furthermore,weare
abletosimulatetheexperimentallyobservedwaveofactivatedNOTCH(NICD)asaresultoftheinteractionsintheGRN.We
esteemourmodelasrobustforawiderangeofparametervalueswiththeHes7mRNAandproteindecaysexertingastrong
influenceonthecoreoscillator.Moreover,ourmodelpredictsinterferencebetweenHes1andHES7oscillatorswhentheir
intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core
oscillatorthatisabletoreproducemanyexperimentallyobserveddatainmice.
Citation:TiedemannHB,SchneltzerE,Zeise
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