Molecular and Mechanical Cues for Somite Periodicity

Abstract

Somitogenesis refers to the segmentation of the paraxial mesoderm, a tissue located on the back of the embryo, into regularly spaced and sized pieces, i.e., the somites. This periodicity is important to assure, for example, the formation of a functional vertebral column. Prevailing models of somitogenesis are based on the existence of a gene regulatory network capable of generating a striped pattern of gene expression, which is subsequently translated into periodic tissue boundaries. An alternative view is that the pre-pattern that guides somitogenesis is not chemical, but of a mechanical origin. A striped pattern of mechanical strain can be formed in physically connected tissues expanding at different rates, as it occurs in the embryo. Here we argue that both molecular and mechanical cues could drive somite periodicity and suggest how they could be integrated.

Keywords: clock and wavefront; differential strain; scaling; somitogenesis; vertebral column.

FIGURE 1

Different molecular models of somitogenesis. In the original clock and wavefront model (C&W), cells oscillate in phase, i.e., the whole paraxial mesoderm would switch “on” or “off” the clock gene at once. The interaction between the clock and the wavefront transforms a whole block of mesenchymal cells into a somite (an epithelial sphere) (A). In the clock and gradient model (C&G), the wavefront is formed by a FGF gradient that progressively regresses toward the tail. Cells synchronize their clocks in a way that they form a stripe of gene expression that sweeps from tail to head. The gradient specifies the position at which the clock slows down and triggers the segmentation program. In contrast to C&W, the wavefront and clock mechanism specifies not a whole somite, but its boundary (B). In the opposing gradients (OG) model, morphogen gradients in opposite directions would form a bistability window in which cells will suddenly change from immature to a mature state if they switch “on” their clocks. This allows the formation of sharp boundaries of gene expression, as those observed in the paraxial mesoderm (C). In the progressive oscillatory reaction-diffusion (PORD) model, prospective boundaries are specified by a repressor emanating from the last formed clock stripe, independently of the FGF gradient (i.e., the gradient does not provides positional information) (D). In the model proposed by Niwa et al. (2011), ERK, a downstream component of FGF signaling, also oscillates. When the ERK oscillation arrives at the anterior region, it inhibits the activation of the segmentation program in mature cells that express the clock. When this oscillation regresses toward the tail, this inhibition is released and cells activate the formation of a somite boundary. In this model the role of FGF signaling is not played by a gradient of positional information, but by the oscillatory behavior of one of its components (E). In Boareto et al. (2021) model the FGF/Wnt gradient does not directly mark the location of a new boundary, however these posterior signals need to be degraded for the intensity of the clock signal to increase (note how the intensity and the thickness of the clock signal decreases along the posteroanterior axis). This increase will trigger the segmentation program. The FGF/Wnt would not provide positional information, but it would regulate the timing of somite formation by means of FGF/Wnt decay rate (F). In the clock and scaled gradient (C&SG), prospective somite boundaries are set by the wavefront alone, by means of a stepwise regression of its downstream component ERK. The role of the clock would be to reinforce this boundaries (G).

FIGURE 2

Mechanical patterning. When mutually adherent tissues expand at different rates (top), a periodic pattern of differential strain capable of driving morphogenesis is created (middle). When the mechanical instabilities are created under compression, one of the tissues forms wrinkles, a characteristic feature of the morphogenesis of some organs (e.g., guts, brain) (bottom) (A). Under tension, these instabilities break up the tissue into regular pieces (cracking), as observed in somitogenesis (bottom) (B).

FIGURE 3

Models of somite boundary specification in the paraxial mesoderm. According to Takahashi and Sato (2008), a somite boundary is marked by a clock-and-wavefront mechanism that triggers the expression of the segmentation program (MESP expression) in the mesenchyme. The epithelium plays a passive role (A) (based on Takahashi and Sato, 2008). In the integrated model suggested in the present work, the epithelium is mechanically patterned by differential strain, and conjointly with a clock-and-wavefront, it marks the location of somite boundary by aligning MESP expression (see the section “Discussion” for details) (B) (green: surrounding tissue; purple: epithelium; cells: mesenchyme; gray fibers: extracellular matrix; MET: mesenchymal-to-epithelial transition).