Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning

PLoS Biol. 2019 Feb 7;17(2):e3000064. doi: 10.1371/journal.pbio.3000064. eCollection 2019 Feb.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning*
  • Chemotaxis
  • Edar Receptor / genetics
  • Edar Receptor / metabolism*
  • Epithelium / embryology
  • Epithelium / metabolism
  • Gene Expression Regulation, Developmental
  • Hair / embryology
  • Mice
  • Mice, Mutant Strains
  • Models, Biological*
  • Signal Transduction*
  • Tooth / embryology*
  • Tooth / metabolism*
  • Tooth Germ / embryology
  • Tooth Germ / metabolism


  • Edar Receptor
  • Edar protein, mouse

Grants and funding

This work received support from Agence Nationale de la Recherche (ANR-06-BLAN-0216 to VL and ANR-11-BSV7-008 to SP), Région Rhône-Alpes (VL), Institut Rhônalpien des Systèmes Complexes (SP), Fondation pour la Recherche Médicale (SP), and Fondation Singer-Polignac (SP). The project was also supported by the Grant Agency of the Czech Republic (14-37368G) (MH). PS was supported by grants 310030_156961 and 310030A_176256 from the Swiss National Science Foundation. This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 639638) (VC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.