Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate

Subjects

Abstract

We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: New rugal stripes appear in the palate at regions of growth.
Figure 2: Rugal stripe patterning size is scaled with growth inhibition and is branched when an established stripe is excised.
Figure 3: Sprouty and Shh loss-of-function mutants implicate FGF and Hedgehog signaling in rugal patterning.
Figure 4: Inhibition of FGF and Hedgehog signaling in palatal explants shows their activatory and inhibitory roles, respectively, in rugal stripe maintenance.

Similar content being viewed by others

References

  1. Turing, A.M. The chemical basis of morphogenesis: a reaction-diffusion model for development. Phil. Trans. R. Soc. Lond. 237, 37–72 (1952).

    Google Scholar 

  2. Kondo, S. & Miura, T. Reaction-diffusion model as a framework for understanding biological pattern formation. Science 329, 1616–1620 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Asai, R., Taguchi, E., Kume, Y., Saito, M. & Kondo, S. Zebrafish Leopard gene as a component of the putative reaction-diffusion system. Mech. Dev. 89, 87–92 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Meinhardt, H. The Algorithmic Beauty of Seashells 4th edn. (Springer-Verlag, 2009).

  5. Kulesa, P.M. et al. On a model mechanism for the spatial patterning of teeth primordia in the alligator. J. Theor. Biol. 180, 287–297 (1996).

    Article  Google Scholar 

  6. Miura, T., Shiota, K., Morriss-Kay, G. & Maini, P.K. Mixed-mode pattern in Doublefoot mutant mouse limb—Turing reaction-diffusion model on a growing domain during limb development. J. Theor. Biol. 240, 562–573 (2006).

    Article  PubMed  Google Scholar 

  7. Jiang, T.X., Jung, H.S., Widelitz, R.B. & Chuong, C.M. Self-organization of periodic patterns by dissociated feather mesenchymal cells and the regulation of size, number and spacing of primordia. Development 126, 4997–5009 (1999).

    CAS  PubMed  Google Scholar 

  8. Sick, S., Reinker, S., Timmer, J. & Schlake, T. WNT and DKK determine hair follicle spacing through a reaction-diffusion mechanism. Science 314, 1447–1450 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Baker, R.E., Schnell, S. & Maini, P.K. Waves and patterning in developmental biology: vertebrate segmentation and feather bud formation as case studies. Int. J. Dev. Biol. 53, 783–794 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Newman, S.A. & Bhat, R. Dynamical patterning modules: a “pattern language” for development and evolution of multicellular form. Int. J. Dev. Biol. 53, 693–705 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Goldbeter, A. & Pourquie, O. Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways. J. Theor. Biol. 252, 574–585 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Axelrod, J.D. Delivering the lateral inhibition punchline: it's all about the timing. Sci. Signal. 3, pe38 (2010).

    Article  PubMed  Google Scholar 

  13. Cohen, M., Georgiou, M., Stevenson, N.L., Miodownik, M. & Baum, B. Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition. Dev. Cell 19, 78–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Pantalacci, S., Semon, M., Martin, A., Chevret, P. & Laudet, V. Heterochronic shifts explain variations in a sequentially developing repeated pattern: palatal ridges of muroid rodents. Evol. Dev. 11, 422–433 (2009).

    Article  PubMed  Google Scholar 

  15. Ikemi, N., Kawata, M. & Yasuda, M. All-trans-retinoic acid-induced variant patterns of palatal rugae in Crj:SD rat fetuses and their potential as indicators for teratogenicity. Reprod. Toxicol. 9, 369–377 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Pospieszny, N., Janeczek, M. & Klećkowska, J. Morphology of the incisive papilla (Papilla incisiva) of pigs during different stages of their prenatal period. EJPAU 6(1), Veterinary#04 (2003).

  17. Pantalacci, S. et al. Patterning of palatal rugae through sequential addition reveals an anterior/posterior boundary in palatal development. BMC Dev. Biol. 8, 116 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Welsh, I.C. & O'Brien, T.P. Signaling integration in the rugae growth zone directs sequential SHH signaling center formation during the rostral outgrowth of the palate. Dev. Biol. 336, 53–67 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rice, D.P., Rice, R. & Thesleff, I. Fgfr mRNA isoforms in craniofacial bone development. Bone 33, 14–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Hosokawa, R. et al. Epithelial-specific requirement of FGFR2 signaling during tooth and palate development. J. Exp. Zool. B. Mol. Dev. Evol. 312B, 343–350 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Simrick, S., Lickert, H. & Basson, M.A. Sprouty genes are essential for the normal development of epibranchial ganglia in the mouse embryo. Dev. Biol. 358, 147–155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Porntaveetus, T., Oommen, S., Sharpe, P.T. & Ohazama, A. Expression of Fgf signalling pathway related genes during palatal rugae development in the mouse. Gene Expr. Patterns 10, 193–198 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Dassule, H.R., Lewis, P., Bei, M., Maas, R. & McMahon, A.P. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 127, 4775–4785 (2000).

    CAS  PubMed  Google Scholar 

  24. Shoji, H., Iwasa, Y. & Kondo, S. Stripes, spots, or reversed spots in two-dimensional Turing systems. J. Theor. Biol. 224, 339–350 (2003).

    Article  PubMed  Google Scholar 

  25. Sinha, S. & Chen, J.K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol. 2, 29–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, Z. et al. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development 129, 4135–4146 (2002).

    CAS  PubMed  Google Scholar 

  27. Lin, C. et al. The inductive role of Wnt–β-catenin signaling in the formation of oral apparatus. Dev. Biol. 356, 40–50 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ishihara, S. & Kaneko, K. Turing pattern with proportion preservation. J. Theor. Biol. 238, 683–693 (2006).

    Article  PubMed  Google Scholar 

  29. Ahn, Y., Sanderson, B.W., Klein, O.D. & Krumlauf, R. Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development 137, 3221–3231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sala, F.G. et al. FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138, 273–282 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Martin, P. Tissue patterning in the developing mouse limb. Int. J. Dev. Biol. 34, 323–336 (1990).

    CAS  PubMed  Google Scholar 

  32. Mootoosamy, R.C. & Dietrich, S. Distinct regulatory cascades for head and trunk myogenesis. Development 129, 573–583 (2002).

    CAS  PubMed  Google Scholar 

  33. Basson, M.A. et al. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev. Cell 8, 229–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Shim, K., Minowada, G., Coling, D.E. & Martin, G.R. Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev. Cell 8, 553–564 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Lander and M. Cohen for useful advice on models, G. Martin (University of California, San Francisco) for the Spry2 mutant mice, M. Kawasaki, Y. Otsuka-Tanaka and K. Kawasaki for assistance with in situ hybridization and M. Miodownik and M. Rubock for critical reading of the manuscript. This work was funded by a Medical Research Council (MRC; UK) grant (G0801154 to J.B.A.G. and M.T.C.).

Author information

Authors and Affiliations

Authors

Contributions

A.D.E. performed palate measurements and explant experiments. T.P., A.O., P.T.S., M.A.B., A.G.-L. and M.T.C. constructed and analyzed the mouse mutants. S.K. performed the modeling. A.D.E., M.T.C. and J.B.A.G. designed the explant experiments and wrote the manuscript, with contributions from the other authors.

Corresponding author

Correspondence to Jeremy B A Green.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 2454 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Economou, A., Ohazama, A., Porntaveetus, T. et al. Periodic stripe formation by a Turing mechanism operating at growth zones in the mammalian palate. Nat Genet 44, 348–351 (2012). https://doi.org/10.1038/ng.1090

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.1090

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing