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.

Department of Biochemistry University of Lausanne CH 1066 Epalinges Switzerland

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Institut Camille Jordan Université de Lyon Université Claude Bernard CNRS UMR 5208 Lyon France

Institut de Génomique Fonctionnelle de Lyon Université de Lyon ENS de Lyon Univ Claude Bernard CNRS UMR 5239 Lyon France

Institute of Experimental Medicine The Czech Academy of Sciences Prague Czech Republic

Laboratoire de Biologie et Modélisation de la Cellule Université de Lyon ENS de Lyon Univ Claude Bernard CNRS UMR 5239 INSERM U1210 Lyon France

Unité de Mathématiques Pures et Appliquées project team Inria NUMED Université de Lyon ENS de Lyon CNRS UMR 5669 Lyon France

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Chapter Wolpert L. 6 Positional Information and Pattern Formation Current Topics in Developmental Biology. Elsevier; 1971. pp. 183–224. 10.1016/S0070-2153(08)60641-9 PubMed DOI

Wolpert L. Positional Information and Pattern Formation Current Topics in Developmental Biology. Elsevier; 2016. pp. 597–608. 10.1016/bs.ctdb.2015.11.008 PubMed DOI

Green JBA, Sharpe J. Positional information and reaction-diffusion: two big ideas in developmental biology combine. Development. 2015;142: 1203–1211. 10.1242/dev.114991 PubMed DOI

Kondo S, Miura T. Reaction-Diffusion Model as a Framework for Understanding Biological Pattern Formation. Science. 2010;329: 1616–1620. 10.1126/science.1179047 PubMed DOI

Turing AM. The chemical basis of morphogenesis. Philos Trans R Soc Lond B Biol Sci. 1952;237: 37–72. PubMed PMC

Duboule D. Time for Chronomics? Science. 2003;301: 277–277. 10.1126/science.301.5631.277 PubMed DOI

Salazar-Ciudad I. Mechanisms of pattern formation in development and evolution. Development. 2003;130: 2027–2037. 10.1242/dev.00425 PubMed DOI

Salazar-Ciudad I, Jernvall J. A computational model of teeth and the developmental origins of morphological variation. Nature. 2010;464: 583–586. 10.1038/nature08838 PubMed DOI

Verd B, Crombach A, Jaeger J. Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression. Umulis D, editor. PLoS Comput Biol. 2017;13: e1005285 10.1371/journal.pcbi.1005285 PubMed DOI PMC

Marcon L, Sharpe J. Turing patterns in development: what about the horse part? Curr Opin Genet Dev. 2012;22: 578–584. 10.1016/j.gde.2012.11.013 PubMed DOI

Glover JD, Wells KL, Matthäus F, Painter KJ, Ho W, Riddell J, et al. Hierarchical patterning modes orchestrate hair follicle morphogenesis. Hill C, editor. PLoS Biol. 2017;15: e2002117 10.1371/journal.pbio.2002117 PubMed DOI PMC

Mou C, Jackson B, Schneider P, Overbeek PA, Headon DJ. Generation of the primary hair follicle pattern. Proc Natl Acad Sci. 2006;103: 9075–9080. 10.1073/pnas.0600825103 PubMed DOI PMC

Economou AD, Ohazama A, Porntaveetus T, Sharpe PT, Kondo S, Basson MA, et al. Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate. Nat Genet. 2012;44: 348–351. 10.1038/ng.1090 PubMed DOI PMC

Rushikesh Sheth, Marcon L, Bastida MF, Junco M, Quintana L, Dahn Randall, et al. Hox Genes Regulate Digit Patterning by Controlling the Wavelength of a Turing-Type Mechanism. Science. 2012;338: 1476–1480. 10.1126/science.1226804 PubMed DOI PMC

Cotterell J, Robert-Moreno A, Sharpe J. A Local, Self-Organizing Reaction-Diffusion Model Can Explain Somite Patterning in Embryos. Cell Syst. 2015;1: 257–269. 10.1016/j.cels.2015.10.002 PubMed DOI

Meinhardt H, Gierer A. Pattern formation by local self-activation and lateral inhibition. Bioessays. 2000;22: 753–760. 10.1002/1521-1878(200008)22:8<753::AID-BIES9>3.0.CO;2-Z PubMed DOI

Eom DS, Bain EJ, Patterson LB, Grout ME, Parichy DM. Long-distance communication by specialized cellular projections during pigment pattern development and evolution. eLife. 2015;4 10.7554/eLife.12401 PubMed DOI PMC

Nakamasu A, Takahashi G, Kanbe A, Kondo S. Interactions between zebrafish pigment cells responsible for the generation of Turing patterns. Proc Natl Acad Sci. 2009;106: 8429–8434. 10.1073/pnas.0808622106 PubMed DOI PMC

Hillen T, Painter KJ. A user’s guide to PDE models for chemotaxis. J Math Biol. 2009;58: 183–217. 10.1007/s00285-008-0201-3 PubMed DOI

Keller EF, Segel LA. Initiation of slime mold aggregation viewed as an instability. J Theor Biol. 1970;26: 399–415. 10.1016/0022-5193(70)90092-5 PubMed DOI

Patlak C. Random walk with persistence and external bias. Bull Math Biophys. 1953;15: 311–338.

Painter KJ, Ho W, Headon DJ. A chemotaxis model of feather primordia pattern formation during avian development. J Theor Biol. 2018;437: 225–238. 10.1016/j.jtbi.2017.10.026 PubMed DOI

Rodrigues HG, Charles C, Marivaux L, Vianey-Liaud M, Viriot L. Evolutionary and developmental dynamics of the dentition in Muroidea and Dipodoidea (Rodentia, Mammalia): Evo-devo of muroid and dipodoid teeth. Evol Dev. 2011;13: 361–369. 10.1111/j.1525-142X.2011.00491.x PubMed DOI

Gaete M, Fons JM, Popa EM, Chatzeli L, Tucker AS. Epithelial topography for repetitive tooth formation. Biol Open. 2015;4: 1625–1634. 10.1242/bio.013672 PubMed DOI PMC

Lesot H, Vonesch JL, Peterka M, Tureckova J, Peterkova R, Ruch JV. Mouse molar morphogenesis revisited by three-dimensional reconstruction. II. Spatial distribution of mitoses and apoptosis in cap to bell staged first and second upper molar teeth. Int J Dev Biol. 1996;40: 1017–1031. PubMed

Peterkova R, Lesot H, Vonesch JL, Peterka M, Ruch JV. Mouse molar morphogenesis revisited by three dimensional reconstruction. I. Analysis of initial stages of the first upper molar development revealed two transient buds. Int J Dev Biol. 1996;40: 1009–1016. PubMed

O’Connell DJ, Ho JWK, Mammoto T, Turbe-Doan A, O’Connell JT, Haseley PS, et al. A Wnt-bmp feedback circuit controls intertissue signaling dynamics in tooth organogenesis. Sci Signal. 2012;5: ra4 10.1126/scisignal.2002414 PubMed DOI PMC

Mammoto T, Mammoto A, Torisawa Y, Tat T, Gibbs A, Derda R, et al. Mechanochemical Control of Mesenchymal Condensation and Embryonic Tooth Organ Formation. Dev Cell. 2011;21: 758–769. 10.1016/j.devcel.2011.07.006 PubMed DOI PMC

Biggs LC, Mikkola ML. Early inductive events in ectodermal appendage morphogenesis. Semin Cell Dev Biol. 2014;25–26: 11–21. 10.1016/j.semcdb.2014.01.007 PubMed DOI

Kavanagh KD, Evans AR, Jernvall J. Predicting evolutionary patterns of mammalian teeth from development. Nature. 2007;449: 427–432. 10.1038/nature06153 PubMed DOI

Cho S-W, Kwak S, Woolley TE, Lee M-J, Kim E-J, Baker RE, et al. Interactions between Shh, Sostdc1 and Wnt signaling and a new feedback loop for spatial patterning of the teeth. Development. 2011;138: 1807–1816. 10.1242/dev.056051 PubMed DOI

Navarro N, Murat Maga A. Genetic mapping of molar size relations identifies inhibitory locus for third molars in mice. Heredity. 2018;121: 1–11. 10.1038/s41437-017-0033-2 PubMed DOI PMC

Prochazka J, Pantalacci S, Churava S, Rothova M, Lambert A, Lesot H, et al. Patterning by heritage in mouse molar row development. Proc Natl Acad Sci. 2010;107: 15497–15502. 10.1073/pnas.1002784107 PubMed DOI PMC

Viriot L, Lesot H, Vonesch JL, Ruch J-V, Peterka M, Peterkova R. The presence of rudimentary odontogenic structures in the mouse embryonic mandible requires reinterpretation of developmental control of first lower molar histomorphogenesis. Int J Dev Biol. 2002;44: 233–240. PubMed

Peterkova R, Lesot H, Peterka M. Phylogenetic memory of developing mammalian dentition. J Exp Zoolog B Mol Dev Evol. 2006;306B: 234–250. 10.1002/jez.b.21093 PubMed DOI

Lochovska K, Peterkova R, Pavlikova Z, Hovorakova M. Sprouty gene dosage influences temporal-spatial dynamics of primary enamel knot formation. BMC Dev Biol. 2015;15 10.1186/s12861-015-0070-0 PubMed DOI PMC

Cobourne MT, Sharpe PT. Making up the numbers: The molecular control of mammalian dental formula. Semin Cell Dev Biol. 2010;21: 314–324. 10.1016/j.semcdb.2010.01.007 PubMed DOI

Peterková R, Lesot H, Viriot L, Peterka M. The supernumerary cheek tooth in tabby/EDA mice—a reminiscence of the premolar in mouse ancestors. Arch Oral Biol. 2005;50: 219–225. 10.1016/j.archoralbio.2004.10.020 PubMed DOI

Peterkova R, Churava S, Lesot H, Rothova M, Prochazka J, Peterka M, et al. Revitalization of a diastemal tooth primordium in Spry2 null mice results from increased proliferation and decreased apoptosis. J Exp Zoolog B Mol Dev Evol. 2009;312B: 292–308. 10.1002/jez.b.21266 PubMed DOI PMC

Ahn Y, Sanderson BW, Klein OD, Krumlauf R. Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development. 2010;137: 3221–3231. 10.1242/dev.054668 PubMed DOI PMC

Haara O, Harjunmaa E, Lindfors PH, Huh S-H, Fliniaux I, Aberg T, et al. Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling. Development. 2012;139: 3189–3199. 10.1242/dev.079558 PubMed DOI PMC

Lagronova-Churava S, Spoutil F, Vojtechova S, Lesot H, Peterka M, Klein OD, et al. The dynamics of supernumerary tooth development are differentially regulated by Sprouty genes. J Exp Zoolog B Mol Dev Evol. 2013;320: 307–320. PubMed

Lefebvre S, Mikkola ML. Ectodysplasin research—Where to next? Semin Immunol. 2014;26: 220–228. 10.1016/j.smim.2014.05.002 PubMed DOI

Sadier A, Viriot L, Pantalacci S, Laudet V. The ectodysplasin pathway: from diseases to adaptations. Trends Genet. 2014;30: 24–31. 10.1016/j.tig.2013.08.006 PubMed DOI

Schmidt-Ullrich R. NF- B transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth. Development. 2006;133: 1045–1057. 10.1242/dev.02278 PubMed DOI

Zhang Y, Tomann P, Andl T, Gallant NM, Huelsken J, Jerchow B, et al. Reciprocal Requirements for EDA/EDAR/NF-κB and Wnt/β-Catenin Signaling Pathways in Hair Follicle Induction. Dev Cell. 2009;17: 49–61. 10.1016/j.devcel.2009.05.011 PubMed DOI PMC

Laurikkala J, Mikkola M, Mustonen T, Åberg T, Koppinen P, Pispa J, et al. TNF Signaling via the Ligand–Receptor Pair Ectodysplasin and Edar Controls the Function of Epithelial Signaling Centers and Is Regulated by Wnt and Activin during Tooth Organogenesis. Dev Biol. 2001;229: 443–455. 10.1006/dbio.2000.9955 PubMed DOI

Ahtiainen L, Lefebvre S, Lindfors PH, Renvoisé E, Shirokova V, Vartiainen MK, et al. Directional Cell Migration, but Not Proliferation, Drives Hair Placode Morphogenesis. Dev Cell. 2014;28: 588–602. 10.1016/j.devcel.2014.02.003 PubMed DOI

Ahtiainen L, Uski I, Thesleff I, Mikkola ML. Early epithelial signaling center governs tooth budding morphogenesis. J Cell Biol. 2016;214: 753–767. 10.1083/jcb.201512074 PubMed DOI PMC

Harjunmaa E, Seidel K, Häkkinen T, Renvoisé E, Corfe IJ, Kallonen A, et al. Replaying evolutionary transitions from the dental fossil record. Nature. 2014; 10.1038/nature13613 PubMed DOI PMC

Tucker AS, Headon DJ, Schneider P, Ferguson BM, Overbeek P, Tschopp J, et al. Edar/Eda interactions regulate enamel knot formation in tooth morphogenesis. Development. 2000;127: 4691–4700. PubMed

Kangas AT, Evans AR, Thesleff I, Jernvall J. Nonindependence of mammalian dental characters. Nature. 2004;432: 211–214. 10.1038/nature02927 PubMed DOI

Charles C, Pantalacci S, Tafforeau P, Headon D, Laudet V, Viriot L. Distinct Impacts of Eda and Edar Loss of Function on the Mouse Dentition. Bauchet M, editor. PLoS ONE. 2009;4: e4985 10.1371/journal.pone.0004985 PubMed DOI PMC

Charles C, Pantalacci S, Peterkova R, Tafforeau P, Laudet V, Viriot L. Effect of eda Loss of Function on Upper Jugal Tooth Morphology. Anat Rec Adv Integr Anat Evol Biol. 2009;292: 299–308. 10.1002/ar.20804 PubMed DOI

Kristenová P, Peterka M, Lisi S, Gendrault JL, Lesot H, Peterková R. Different morphotypes of functional dentition in the lower molar region of tabby (EDA) mice. Orthod Craniofac Res. 2002;5: 205–214. PubMed

Pummila M, Fliniaux I, Jaatinen R, James MJ, Laurikkala J, Schneider P, et al. Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression. Development. 2007;134: 117–125. 10.1242/dev.02708 PubMed DOI

Fliniaux I, Mikkola ML, Lefebvre S, Thesleff I. Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes. Dev Biol. 2008;320: 60–71. 10.1016/j.ydbio.2008.04.023 PubMed DOI

Munne PM, Felszeghy S, Jussila M, Suomalainen M, Thesleff I, Jernvall J. Splitting placodes: effects of bone morphogenetic protein and Activin on the patterning and identity of mouse incisors: Splitting placodes. Evol Dev. 2010;12: 383–392. 10.1111/j.1525-142X.2010.00425.x PubMed DOI

Mikkola ML. Genetic basis of skin appendage development. Semin Cell Dev Biol. 2007;18: 225–236. 10.1016/j.semcdb.2007.01.007 PubMed DOI

Prochazkova M, Häkkinen TJ, Prochazka J, Spoutil F, Jheon AH, Ahn Y, et al. FGF signaling refines Wnt gradients to regulate the patterning of taste papillae. Development. 2017;144: 2212–2221. 10.1242/dev.148080 PubMed DOI PMC

Mina M, Kollar EJ. The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. Arch Oral Biol. 1987;32: 123–127. PubMed

Bei M, Kratochwil K, Maas RL. BMP4 rescues a non-cell-autonomous function of Msx1 in tooth development. Development. 2000;127: 4711–4718. PubMed

Jia S, Zhou J, Gao Y, Baek J-A, Martin JF, Lan Y, et al. Roles of Bmp4 during tooth morphogenesis and sequential tooth formation. Development. 2013;140: 423–432. 10.1242/dev.081927 PubMed DOI PMC

Jia S, Kwon H-JE, Lan Y, Zhou J, Liu H, Jiang R. Bmp4-Msx1 signaling and Osr2 control tooth organogenesis through antagonistic regulation of secreted Wnt antagonists. Dev Biol. 2016;420: 110–119. 10.1016/j.ydbio.2016.10.001 PubMed DOI PMC

Miletich I, Yu W-Y, Zhang R, Yang K, Andrade SC de, Pereira SF do A, et al. Developmental stalling and organ-autonomous regulation of morphogenesis. Proc Natl Acad Sci. 2011;108: 19270–19275. 10.1073/pnas.1112801108 PubMed DOI PMC

Maini PK, Baker RE, Schnell S. Rethinking Models of Pattern Formation in Somitogenesis. Cell Syst. 2015;1: 248–249. 10.1016/j.cels.2015.10.004 PubMed DOI

Maroto M, Dale JK, Dequeant M-L, Petit A-C, Pourquie O. Synchronised cycling gene oscillations in presomitic mesoderm cells require cell-cell contact. Int J Dev Biol. 2005;49: 309–315. 10.1387/ijdb.041958mm PubMed DOI

Pascoal S, Carvalho CR, Rodriguez-León J, Delfini M-C, Duprez D, Thorsteinsdóttir S, et al. A Molecular Clock Operates During Chick Autopod Proximal-distal Outgrowth. J Mol Biol. 2007;368: 303–309. 10.1016/j.jmb.2007.01.089 PubMed DOI

Baker RE, Schnell S, Maini PK. Mathematical Models for Somite Formation Current Topics in Developmental Biology. Elsevier; 2008. pp. 183–203. 10.1016/S0070-2153(07)81006-4 PubMed DOI PMC

Cobourne MT. Restriction of sonic hedgehog signalling during early tooth development. Development. 2004;131: 2875–2885. 10.1242/dev.01163 PubMed DOI

Porntaveetus T, Ohazama A, Choi HY, Herz J, Sharpe PT. Wnt signaling in the murine diastema. Eur J Orthod. 2012;34: 518–524. 10.1093/ejo/cjr049 PubMed DOI PMC

Klein OD, Minowada G, Peterkova R, Kangas A, Yu BD, Lesot H, et al. Sprouty Genes Control Diastema Tooth Development via Bidirectional Antagonism of Epithelial-Mesenchymal FGF Signaling. Dev Cell. 2006;11: 181–190. 10.1016/j.devcel.2006.05.014 PubMed DOI PMC

Li L, Yuan G, Liu C, Zhang L, Zhang Y, Chen Y, et al. Exogenous fibroblast growth factor 8 rescues development of mouse diastemal vestigial tooth ex vivo. Dev Dyn. 2011;240: 1344–1353. 10.1002/dvdy.22596 PubMed DOI PMC

Jacob F. Evolution and Tinkering. 1977;196: 1161–1166. PubMed

Clark E. Dynamic patterning by the Drosophila pair-rule network reconciles long-germ and short-germ segmentation. PLoS Biol. 2017;15: e2002439 10.1371/journal.pbio.2002439 PubMed DOI PMC

Crombach A, García-Solache MA, Jaeger J. Evolution of early development in dipterans: Reverse-engineering the gap gene network in the moth midge Clogmia albipunctata (Psychodidae). Biosystems. 2014;123: 74–85. 10.1016/j.biosystems.2014.06.003 PubMed DOI

Verd B, Clark E, Wotton KR, Janssens H, Jim E. A damped oscillator imposes temporal order on posterior gap gene expression in Drosophila. PLoS Biol. 2018;16: 24 10.1371/journal.pbio.2003174 PubMed DOI PMC

DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development. 1999;126: 4557–4568. PubMed

Headon DJ, Overbeek PA. Involvement of a novel Tnf receptor homologue in hair follicle induction. Nat Genet. 1999;22: 370–374. 10.1038/11943 PubMed DOI

Peterka M, Lesot H, Peterková R. Body weight in mouse embryos specifies staging of tooth development. Connect Tissue Res. 2002;43: 186–190. PubMed

Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ. Evidence for an Expansion-Based Temporal Shh Gradient in Specifying Vertebrate Digit Identities. Cell. 2004;118: 517–528. 10.1016/j.cell.2004.07.024 PubMed DOI

Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993;75: 1417–1430. 10.1016/0092-8674(93)90627-3 PubMed DOI

Kowalczyk-Quintas C, Willen L, Dang AT, Sarrasin H, Tardivel A, Hermes K, et al. Generation and Characterization of Function-blocking Anti-ectodysplasin A (EDA) Monoclonal Antibodies That Induce Ectodermal Dysplasia. J Biol Chem. 2014;289: 4273–4285. 10.1074/jbc.M113.535740 PubMed DOI PMC

Alfaqeeh SA, Tucker AS. The Slice Culture Method for Following Development of Tooth Germs In Explant Culture. J Vis Exp. 2013; 10.3791/50824 PubMed DOI PMC

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