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.

The molecular logic for planarian regeneration along the anterior–posterior axis

Subjects

Abstract

The planarian Dugesia japonica can regenerate a complete individual from a head, trunk or tail fragment via activation of somatic pluripotent stem cells1,2. About a century ago, Thomas Hunt Morgan attempted to explain the extraordinary regenerative ability of planarians by positing two opposing morphogenetic gradients of formative “head stuff” and “tail stuff” along the anterior–posterior axis3,4. However, Morgan’s hypothesis remains open to debate. Here we show that extracellular signal-related kinase (ERK) and Wnt/β-catenin signalling pathways establish a solid framework for planarian regeneration. Our data suggest that ERK signalling forms a spatial gradient in the anterior region during regeneration. The fibroblast growth factor receptor-like gene nou-darake5 (which serves as an output of ERK signalling in the differentiating head) and posteriorly biased β-catenin activity6,7,8 negatively regulate ERK signalling along the anterior–posterior axis in distinct manners, and thereby posteriorize regenerating tissues outside the head region to reconstruct a complete head-to-tail axis. On the basis of this knowledge about D. japonica, we proposed that β-catenin signalling is responsible for the lack of head-regenerative ability of tail fragments in the planarian Phagocata kawakatsui, and our confirmation thereof supports the notion that posterior β-catenin signalling negatively modulates the ERK signalling involved in anteriorization across planarian species. These findings suggest that ERK signalling has a pivotal role in triggering globally dynamic differentiation of stem cells in a head-to-tail sequence through a default program that promotes head tissue specification in the absence of posteriorizing signals. Thus, we have confirmed the broad outline of Morgan’s hypothesis, and refined it on the basis of our proposed default property of planarian stem cells.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: β-catenin signalling affects ERK signalling during regeneration.
Figure 2: Effects of pharmacological ERK inhibition on anterior–posterior patterning during regeneration.
Figure 3: Effects of Djndk RNAi on anterior–posterior patterning during regeneration.
Figure 4: Phenotypes induced by RNAi of β-catenin in different planarian species.

References

  1. Shibata, N., Rouhana, L. & Agata, K. Cellular and molecular dissection of pluripotent adult somatic stem cells in planarians. Dev. Growth Differ. 52, 27–41 (2010)

    CAS  Article  Google Scholar 

  2. Wagner, D. E., Wang, I. E. & Reddien, P. W. Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science 332, 811–816 (2011)

    ADS  CAS  Article  Google Scholar 

  3. Morgan, T. H. “Polarity” considered as a phenomenon of gradation of materials. J. Exp. Zool. 2, 495–506 (1905)

    Article  Google Scholar 

  4. Lawrence, P. A. Background to bicoid. Cell 54, 1–2 (1988)

    CAS  Article  Google Scholar 

  5. Cebrià, F. et al. FGFR-related gene nou-darake restricts brain tissues to the head region of planarians. Nature 419, 620–624 (2002)

    ADS  Article  Google Scholar 

  6. Gurley, K. A., Rink, J. C. & Sánchez Alvarado, A. β-Catenin defines head versus tail identity during planarian regeneration and homeostasis. Science 319, 323–327 (2008)

    ADS  CAS  Article  Google Scholar 

  7. Petersen, C. P. & Reddien, P. W. Smed-βcatenin-1 is required for anteroposterior blastema polarity in planarian regeneration. Science 319, 327–330 (2008)

    ADS  CAS  Article  Google Scholar 

  8. Petersen, C. P. & Reddien, P. W. A wound-induced Wnt expression program controls planarian regeneration polarity. Proc. Natl Acad. Sci. USA 106, 17061–17066 (2009)

    ADS  CAS  Article  Google Scholar 

  9. Kobayashi, C., Nogi, T., Watanabe, K. & Agata, K. Ectopic pharynxes arise by regional reorganization after anterior/posterior chimera in planarians. Mech. Dev. 89, 25–34 (1999)

    CAS  Article  Google Scholar 

  10. Koinuma, S., Umesono, Y., Watanabe, K. & Agata, K. Planaria FoxA (HNF3) homologue is specifically expressed in the pharynx-forming cells. Gene 259, 171–176 (2000)

    CAS  Article  Google Scholar 

  11. Nogi, T. & Watanabe, K. Position-specific and non-colinear expression of the planarian posterior (Abdominal-B-like) gene. Dev. Growth Differ. 43, 177–184 (2001)

    CAS  Article  Google Scholar 

  12. Nishimura, K. et al. Reconstruction of dopaminergic neural network and locomotion function in planarian regenerates. Dev. Neurobiol. 67, 1059–1078 (2007)

    CAS  Article  Google Scholar 

  13. Agata, K. & Umesono, Y. Brain regeneration from pluripotent stem cells in planarian. Phil. Trans. R. Soc. Lond. B 363, 2071–2078 (2008)

    CAS  Article  Google Scholar 

  14. Umesono, Y. & Agata, K. Evolution and regeneration of the planarian central nervous system. Dev. Growth Differ. 51, 185–195 (2009)

    CAS  Article  Google Scholar 

  15. Agata, K., Saito, Y. & Nakajima, E. Unifying principles of regeneration I: epimorphosis versus morphallaxis. Dev. Growth Differ. 49, 73–78 (2007)

    Article  Google Scholar 

  16. Agata, K., Tanaka, T., Kobayashi, C., Kato, K. & Saitoh, Y. Intercalary regeneration in planarians. Dev. Dyn. 226, 308–316 (2003)

    CAS  Article  Google Scholar 

  17. Sánchez Alvarado, A. & Newmark, P. A. Double-stranded RNA specifically disrupts gene expression during planarian regeneration. Proc. Natl Acad. Sci. USA 96, 5049–5054 (1999)

    ADS  Article  Google Scholar 

  18. Rouhana, L. et al. RNA interference by feeding in vitro-synthesized double-stranded RNA to planarians: methodology and dynamics. Dev. Dyn. 242, 718–730 (2013)

    CAS  Article  Google Scholar 

  19. Yazawa, S., Umesono, Y., Hayashi, T., Tarui, H. & Agata, K. Planarian Hedgehog/Patched establishes anterior-posterior polarity by regulating Wnt signaling. Proc. Natl Acad. Sci. USA 106, 22329–22334 (2009)

    ADS  CAS  Article  Google Scholar 

  20. Tasaki, J. et al. ERK signaling controls blastema cell differentiation during planarian regeneration. Development 138, 2417–2427 (2011)

    CAS  Article  Google Scholar 

  21. Morgan, T. H. The control of heteromorphosis in Planaria maculata. Arch. Entw. Mech. Org. 17, 683–695 (1904)

    Google Scholar 

  22. Agata, K. & Inoue, T. Survey of the differences between regenerative and non-regenerative animals. Dev. Growth Differ. 54, 143–152 (2012)

    CAS  Article  Google Scholar 

  23. Inoue, T. et al. Morphological and functional recovery of the planarian photosensing system during head regeneration. Zoolog. Sci. 21, 275–283 (2004)

    CAS  Article  Google Scholar 

  24. Takano, T. et al. Regeneration-dependent conditional gene knockdown (Readyknock) in planarian: demonstration of requirement for Djsnap-25 expression in the brain for negative phototactic behavior. Dev. Growth Differ. 49, 383–394 (2007)

    CAS  Article  Google Scholar 

  25. Umesono, Y., Watanabe, K. & Agata, K. A planarian orthopedia homolog is specifically expressed in the branch region of both the mature and regenerating brain. Dev. Growth Differ. 39, 723–727 (1997)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank C. Hashimoto for discussions and comments. We also thank E. Nakajima and A. Alié for critical reading of the manuscript, Y. Saito for illustrations, and all of our other laboratory members for their help and encouragement. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas to Y.U. (22124004), a Grant-in-Aid for Scientific Research on Innovative Areas to K.A. (22124001), a Grant-in-Aid for Creative Scientific Research to K.A. (17GS0318), Global COE Program A06 of Kyoto University, the Naito Foundation, a Sasakawa Scientific Research Grant, and a JSPS Research Fellowship to J.T.

Author information

Authors and Affiliations

Authors

Contributions

Y.U. and K.A. designed the study. Y.U., J.T. and K.H. performed the study in D. japonica. S.Y., E.K. and O.N. performed P. kawakatsui transcriptome analysis. Y.U., J.T. Y.N. and M.H. performed the study in P. kawakatsui. T.I. performed behavioural assays. Y.U. wrote the paper.

Corresponding author

Correspondence to Yoshihiko Umesono.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11. (PDF 27637 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Umesono, Y., Tasaki, J., Nishimura, Y. et al. The molecular logic for planarian regeneration along the anterior–posterior axis. Nature 500, 73–76 (2013). https://doi.org/10.1038/nature12359

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12359

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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