Abstract
When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator–inhibitor pair subject to reaction–diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2–M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.
Highlights
The emergence of ordered patterns in multicellular organisms has been a major field of research in developmental biology, revealing a diversity of pattern formation mechanisms
We studied the temporal dynamics of Edar gene expression, the receptor of the Eda pathway, during molar pattern formation and showed that it recalls the dynamics observed during hair patterning
At 14.5 days post coitum, Edar expression is restricted to the primary signaling center (PEK) of the first molar, and no expression is seen in the second molar field, which looks like a "tail" (Fig 1C)
Summary
The emergence of ordered patterns in multicellular organisms has been a major field of research in developmental biology, revealing a diversity of pattern formation mechanisms. Others rely on self-organization, resulting in spontaneous pattern formation as seen in reaction–diffusion (RD) (Turing) mechanisms or upon chemotaxis (see below and [3,4,5]). Temporal dynamics of pattern formation have been more or less emphasized. In most cases patterning is viewed as a directional temporal process: from a prepattern or a spatial heterogeneity emerges the final pattern, which is stabilized. It is, questionable whether biological systems, which result from a historical, contingent process, proceed in such a directional manner, or if transient patterns can be constructed and deconstructed during embryogenesis until the final pattern is formed. A careful reexamination of the example of simultaneous pattern formation, namely the formation of Drosophila gap gene expression pattern, revealed that, as maternal inputs decay, gene expression patterns change with important consequences for the final pattern [9]
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