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



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.

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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.


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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.

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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.

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Correspondence to Yoshihiko Umesono.

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

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