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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - RegEvolve (Comparative analysis of planarian regeneration - why some worms regenerate while others donâ€™t)

Teaser

Summary

Many animals have the ability to regenerate body parts lost as a result of accidents and injuries. However, many animals including humans do not have this ability. This raises a big and largely unresolved question: Why is it that in a world dominated by survival of the fittest, regeneration is the exception rather than the rule?
RegEvolve systematically explores this question by example of planarian flatworms. Planarians are a common group of worms that occur worldwide in fresh water, land and marine eco systems. Some planarian species have the astonishing ability to regenerate complete and perfectly proportioned animals from tiny tissue pieces. However, other planarian species cannot regenerate. Comparisons between regenerating and non-regenerating species therefore provide unique opportunities to ask how regeneration works in the first place, what goes wrong in regeneration deficient species and finally, why some worms regenerate while others do not. RegEvolve will explore these three questions with a specific focus on the Wnt signalling pathway, which we have previously shown to be a critical mediator of planarian regeneration and regeneration defects. Overall, RegEvolve will provide fundamental insights into the molecular orchestration of regeneration and the principles that govern the evolution of the trait in the case of planarians.

Work performed

The specific aims of RegEvolve are:
1) Comparisons of Wnt pathway activity between regenerating and non-regenerating species;
2) Comparative analysis of the genomic mechanisms regulating pathway deployment in regenerating- vs. non-regenerating species;
3) Using our live collection of > 50 species, to systematically explore the correlation of Wnt signalling levels and gene expression signatures with planarian regeneration defects.
With respect to the first aim, we have carried out a comprehensive analysis of Wnt signalling in the regeneration-competent model species S. mediterranea. We found that Wnt signalling establishes a tail to head gradient and that this gradient patterns gene expression along the A/P axis. Further, our findings suggest that the gradient is a self-organizing pattern that interacts in a mutually antagonistic manner with a similar pattern in the head. Our manuscript was published in Developmental Cell and these findings now provide an important baseline for the comparative evaluation of Wnt signalling in non-regenerating species during the next reporting period.

With respect to the second aim, our major achievement during the past reporting period has been the completion of the genome of the model species Schmidtea mediterranea. Our assembly is the first megabase assembly of a free-living flatworm and represents a key resource for the comparative aspect of RegEvolve, as well as the entire planarian research community. We will now use the our established technology to sequence additional planarian genomes, in parallel with the functional analysis of Wnt pathway component deployment during regeneration.

With respect to the third aim, we have determined the phylogeny of our planarian collection on basis of systematic transcriptome sequencing and analysis. Further, we have measured regenerative abilities of all species. Together, these data indicate that whole-body regeneration may have evolved de novo at the base of the fresh water groups, but got lost again in multiple independent lineages. Further, our data so far indicate that all planarian head regeneration defects are due to excessive Wnt signalling, since they can be rescued by b-Catenin RNAi. The finding that regeneration defects represent independent changes of Wnt pathway activity is strategically important for RegEvolve, as it confirms the central hypothesis of the proposal and now allows us to focus on the underlying mechanisms

Final results

RegEvolve is a basic research project that aims to contribute insights to the basic question why in a world shaped by survival of the fittest, regeneration is the exception rather than the rule. To our knowledge, our systematic analysis of the regenerative abilities of >50 planarian species in terms of phylogeny, genomic information and molecular mechanisms is so far unparalleled in breadth and depth.