The Clock and Wavefront Model of Somitogenesis
The molecular mechanism governing somite formation was first proposed as a theoretical model in 1976, called the clock and wavefront model (Cooke and Zeeman, 1976). The clock represents a molecular oscillator, where individual presomitic cells cycle between on and off states of the expression of critical genes. The wavefront marks an important activity threshold at the anterior extent of a posterior-to-anterior signaling gradient that emanates from the posterior terminus of the embryo. During posterior extension, presomitic cells are displaced anteriorly. As this occurs, the molecular oscillator within these cells slows; when it becomes sufficiently slow—and when the displaced cells intersect with the wavefront—a border forms and creates a new somite (explained in more detail in Section 5.6) (Figure 5.2). Several molecules have been discovered that fit the predicted role of either the clock or the wavefront (Aulehla and Pourquie, 2010; Hubaud and Pourquie, 2014; Maroto et al., 2012; Oates et ah, 2012; Pourquie, 2018). In particular, the hairy/enhancer of split genes (referred
FIGURE 5.2 The clock and wavefront mechanism of somitogenesis. (A) A schematic illustrating the relative positions of the somites, the presomitic mesoderm, and the posteriorly localized neuromesodermal progenitors and mesodermal progenitors. The posterior-to-ante- rior gradient of Wnt and FGF signaling is also illustrated. (B) A series of four time points are shown during the formation of one somite. Individual cells have on/off cycling gene expression represented by the blue color (on) or white (off). The cycling expression is coordinated with neighbor cells, and as they cycle they give the impression of a traveling wave of gene expression through the presomitic mesoderm. Cells in the anteriormost stripe stop cycling and remain in the on state, and when these cells drop below a threshold level of wavefront signal, a new somite border is formed. In the schematic, SI is the most recently formed somite. Somites continue to form in the posterior direction at the same time as the axis is extending in the posterior direction. The schematics are shown from a ventral view with posterior to the bottom and anterior to the top.
to as Hes in mouse and chick and her zebrafish) oscillate in the presomitic mesoderm and are a core component of the molecular clock governing somitogenesis (Mara and Holley, 2007; Oates et ah, 2012; Pourquie, 2011). These genes encode bHLH transcriptional repressors that can repress their own transcription. The wavefront is produced from signals emanating from the posteriormost region of the embryo (called the tailbud), notably FGF and canonical Wnt signaling (Aulehla and Pourquie, 2010). Low levels of signal create a threshold value that initiates somite border formation at a particular phase of her/Hes oscillation. As paraxial mesoderm progenitor cells exit the tailbud, they are displaced anteriorly with respect to the tailbud and pass through the signaling gradient.
The cycling of the her/Hes genes begins in the mesodermal progenitors within the tailbud. Subsequently, as cells exit from the tailbud into the unsegmented paraxial mesoderm (called the presomitic mesoderm and abbreviated PSM), oscillations continue but become out of phase with the mesoderm in the tailbud. This cycling activity gives the impression of waves of gene expression through the presomitic mesoderm (Mara and Holley, 2007) (Figure 5.2). The oscillations of gene expression slow as cells mature in the PSM. When the wavefront of FGF and Wnt signaling passes through the PSM and intersects with a permissive oscillatory state of the clock, a new physical boundary is formed, thus creating a new somite (Aulehla and Pourquie, 2010). In the mouse, boundary formation is accomplished by the activation of the Mesp2 gene, which establishes the anterior limit of expression of Thx6 (Saga, 2012; Saga et al., 1997). In cells where Tbx6 is inactivated, border formation occurs. The situation is slightly different in zebrafish, where a quadruple knockout of all the mesp genes causes only mild somite defects (Yabe et al., 2016). In zebrafish, the anterior limit of tbx6 expression also plays a critical role in border formation, but the expression domain is independent of mesp function (Kinoshita et al., 2018; Yabe et al., 2016).