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

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

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Laboratoire de Biologie et Modélisation de la Cellule, Université de Lyon, ENS de Lyon, Univ Claude Bernard, CNRS UMR 5239, INSERM U1210, Lyon, France.
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, ENS de Lyon, Univ Claude Bernard, CNRS UMR 5239, Lyon, France.
Unité de Mathématiques Pures et Appliquées, project team Inria NUMED, Université de Lyon, ENS de Lyon, CNRS UMR 5669, Lyon, France.
Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic.
Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
Institut Camille Jordan, Université de Lyon, Université Claude Bernard, CNRS UMR 5208, Lyon, France.


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.

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