Practical lessons from theoretical models about the somitogenesis

Abstract

Vertebrae and other mammalian repetitive structures are formed from embryonic organs called somites. Somites arise sequentially from the unsegmented presomitic mesoderm (PSM). In mice, a new bilateral pair of somites arise every two hours from the rostral PSM. On the other hand, cells are added to the caudal side of the PSM due to cell proliferation of the tail bud. Somite formation correlates with cycles of cell-autonomous expression in the PSM of genes like Hes7. Because the somitogenesis is a highly dynamic and coordinated process, this event has been subjected to extensive theoretical modeling. Here, we describe the current understanding about the somitogenesis in mouse embryos with an emphasis on insights gained from computer simulations. It is worth noting that the combination of experiments and computer simulations has uncovered dynamical properties of the somitogenesis clock such as the transcription/translation delays, the half-life and the synchronization mechanism across the PSM. Theoretical models have also been useful to provide predictions and rigorous hypothesis about poorly understood processes such as the mechanisms by which the temporal PSM oscillations are arrested and converted into an spatial pattern. We aim at reviewing this theoretical literature in such a way that experimentalists might appreciate the resulting conclusions.

Keywords: Fgf signaling; Hes7 oscillation; Notch signaling; Theoretical models; Wnt signaling; mouse somitogenesis.

Figure1

(a) This drawing represents the tail of a mouse embryo. The somites and the neural tube can be recognized morphologically. To visualize the boundary of the forming somite, molecular markers such as Mesp2 expression are needed. Finally, the tail bud refers to the tip of the tail, where extensive proliferation occurs. S−1, S0, S1,… are terms commonly used to refer to the somites. S0 is the forming somite, S1 the newest somite, etc. (b) Waves of cell-autonomous gene expression (blue) spread from the caudal to the rostral PSM, with a period that correlates with that of the somite formation. Cells do not actively move. However, only tail bud cells extensively proliferate, so that the distance of a cell (red) to the tail bud increases whereas the distance to the somite decreases.

Figure 2

At least, five negative and one positive intracellular feedback loops act in the mouse PSM. The five negative feedback loops are thought to drive the oscillations: Hes7 on itself; Lfng and Notch1; β-Cat and Axin2; ras/Raf1, Erk1/2 and Spry2; Erk1/2 and Dusp6. On the other hand, the interactions from Hes7 to Lfng, Lfng to Notch1 and Notch1 to Hes7 create an intracellular positive feedback loop, which probably couples the oscillations within the Notch pathway. Furthermore, an intercellular positive feedback loop via the Notch pathway has been hypothesized to synchronize neighboring cells. Green and red arrows represent positive and negative interactions, respectively. White and black gene products represent neighboring cells.

Figure 3

Three critical features have been suggested for the Hes1/7 oscillation: The characteristic time delays of eukaryotic transcription/translation, an appropriate short half-life of both mRNA and protein, and finally a well-defined cooperative binding (Hill) coefficient of the protein to its promoter, which might depend, for instance on the number of binding sites.

Figure 4

In this model, two PSM positions P₁ and P₂ are defined by a Fgf8 threshold value and a time delay, respectively. After reaching the second position P₂, cells send a diffusive signal to which only cells between the P₁ and P₂ (gray cells) are able to respond.