Branch Mode Selection during Early Lung Development 英文参考文献.docVIP

BranchModeSelectionduringEarlyLungDevelopment DenisMenshykau1,ConradinKraemer1,DagmarIber1,2* 1DepartmentforBiosystemsScienceandEngineering,ETHZurich,Basel,Switzerland,2SIB,Basel,Switzerland Abstract Manyorgansofhigherorganisms,suchasthevascularsystem,lung,kidney,pancreas,liverandglands,areheavilybranched structures.Thebranchingprocessduringlungdevelopmenthasbeenstudiedingreatdetailandisremarkablystereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of theregulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governslungbranchingmorphogenesis.Themodelfocusesonthetwokeysignalingfactorsthathavebeenidentifiedin experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domainshapearebasedonexperimentaldatawhereavailable.Thedevelopedmodelisrobusttosmallabsoluteandlarge relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching betweenbranchingmodescanbeachievedbytargetedchangesintheparametervalues.Wenotethatthesequenceof differentbranchingeventsmayalsobetheresultofdifferentgrowthspeeds:fastgrowthtriggerslateralbranchingwhile slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate patternthatcorrespondtotheobservedbranchingmodes. Citation: Menshykau D, Kraemer C, Iber D (2012) Branch Mode Selection during Early