title: From dynamic expression patterns to boundary formation in the presomitic mesoderm.
abstract: The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that 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 postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice.
authors: Institute of Experimental Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors: Hendrik B
authors: HB
authors: Tiedemann
authors: Elida
authors: E
authors: Schneltzer
authors: Stefan
authors: S
authors: Zeiser
authors: Bastian
authors: B
authors: Hoesel
authors: Johannes
authors: J
authors: Beckers
authors: Gerhard K H
authors: GK
authors: Przemeck
authors: Martin Hrabě
authors: MH
authors: de Angelis
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology*; D019295:Computational Biology; D003198:Computer Simulation; D025461:Feedback, Physiological; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019170:Somites / Q000196:embryology / Q000378:metabolism; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051524:Fibroblast Growth Factor 8; D012333:RNA, Messenger; D060509:Wnt3A Protein; C496457:Fgf8 protein, mouse; C430525:Hes7 protein, mouse; C107407:Mesp2 protein, mouse; C555511:Wnt3a protein, mouse