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On the difficulty of increasing dental complexity


One of the fascinating aspects of the history of life is the apparent increase in morphological complexity through time1, a well known example being mammalian cheek tooth evolution2,3,4. In contrast, experimental studies of development more readily show a decrease in complexity, again well exemplified by mammalian teeth, in which tooth crown features called cusps are frequently lost in mutant and transgenic mice5,6,7. Here we report that mouse tooth complexity can be increased substantially by adjusting multiple signalling pathways simultaneously. We cultured teeth in vitro and adjusted ectodysplasin (EDA), activin A and sonic hedgehog (SHH) pathways, all of which are individually required for normal tooth development. We quantified tooth complexity using the number of cusps and a topographic measure of surface complexity8. The results show that whereas activation of EDA and activin A signalling, and inhibition of SHH signalling, individually cause subtle to moderate increases in complexity, cusp number is doubled when all three pathways are adjusted in unison. Furthermore, the increase in cusp number does not result from an increase in tooth size, but from an altered primary patterning phase of development. The combination of a lack of complex mutants5,6,7, the paucity of natural variants with complex phenotypes9, and our results of greatly increased dental complexity using multiple pathways, suggests that an increase may be inherently different from a decrease in phenotypic complexity.

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Figure 1: Cusp number can be increased in cultured teeth.
Figure 2: Number and density of cusps increase with the number of adjusted signalling pathways.
Figure 3: Tomography reveals high surface complexity of treated molars.


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We thank I. Thesleff, P. Munne, A. R. Evans, I. Corfe, J. Moustakas, M. Murtoniemi, I. Salazar-Ciudad, S. Sova, J.-P. Suuronen and S. Zohdy for discussions or help; R. Santalahti, R. Savolainen and M. Mäkinen for technical assistance; M. Hyvönen for the activin A protein; P. Schneider for the Fc-EDA-A1-protein; and C. Tabin and A. Gritli-Linde for the ShhGFP mice. This study was funded by the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cultural Foundation, and the graduate school GSBM.

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Authors and Affiliations



E.H. and J.J. designed the study. E.H. performed developmental experiments and measurements. M.L.M. and M.V. designed and performed Eda;Edar transgenic mouse experiments. K.H. and A.K. designed and performed microtomography imaging. E.H. and J.J. analysed the data and wrote the manuscript with contributions from the other authors. J.J. coordinated the study.

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Correspondence to Jukka Jernvall.

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The authors declare no competing financial interests.

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Harjunmaa, E., Kallonen, A., Voutilainen, M. et al. On the difficulty of increasing dental complexity. Nature 483, 324–327 (2012).

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