From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

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.
Author Summary Somitogenesis is a process in embryonic development establishing the segmentation of the vertebrate body by the periodic separation of small balls of epithelialized cells called somites from a growing mesenchymal tissue, the presomitic mesoderm (PSM). The basic mechanisms are often discussed in terms of the clock-and-wave-front model, which was proposed already in 1976. Candidate genes for this model were found only in the last fifteen years with the cyclically expressed Hairy/Hes genes functioning as the clock and posteriorly expressed Fgf, Tbx6, and Wnt genes establishing the gradient(s). In addition, the Delta/Notch signal transduction pathway seems to be important for boundary formation between forming somites and the remaining PSM by inducing Mesp2 expression just behind a future somitic boundary. Although many in silico models describing partial aspects of somitogenesis already exist, there are still conflicts regarding the mechanisms of the somitogenesis clock. Furthermore, a simulation that fully integrates clock and gradient was only recently published for chicken. Here, we propose a cell- and gene-based computer model for mammalian somitogenesis, simulating a gene regulatory network combining clock (Hes1/7) and gradient (Tbx6, Fgf8, Wnt3a) with Delta/Notch signaling resulting in dynamic gene expression patterns as observed in vivo finally leading to boundary formation.