Nontechnical paragraph: Regeneration is a fascinating phenomenon whereby an adult animal makes new cells and structures in response to injury. This project focuses on understanding, at the cellular level, how the earliest responses upon injury lead to correct regeneration of missing tissues. How does the animal know that it has lost organs and how does it make the right cells in the right places? Although many animal species can regenerate, the details of the underlying molecular pathways and how these pathways compare across species remain unknown. Biological pathways acquire changes in all species over the course of many generations, but evolution tends to preserve pathways that are essential. Therefore, by studying two species of distantly-related worms that both have impressive regeneration abilities, this project will reveal which aspects of regeneration are shared, and hence essential. The general principles of regeneration identified through this work will have relevance to regenerative medicine. In addition to the training of students and postdoctoral researchers involved in this research, the broader impacts of this project include providing hands-on experiences with molecular studies of evolutionary biology to students at local public schools. Teachers will receive training, equipment, supplies, and staff support to implement curriculum that incorporates experimental molecular biology. Direct experiences with how science is practiced in research labs will enhance retention of students in STEM fields.

Technical paragraph: Many extant lineages of animals can regenerate any missing cell type, raising the possibility that the earliest animals to evolve were capable of "whole-body" regeneration. Functional studies of multiple species in phylogenetically informative positions relative to each other are needed to evaluate how the gene regulatory networks (GRNs) underlying regeneration have evolved. This research will leverage the planarian Schmidtea mediterranea and the acoel Hofstenia miamia; both regenerate all missing tissues, are easy to culture, and offer high-throughput screening of gene function via RNAi. Importantly, Hofstenia offers an additional advantage: the availability of accessible embryos, which will enable functional studies of regulatory DNA proposed here. Acoels represent the earliest lineage of animals with bilateral symmetry (Bilateria), and therefore, comparisons of acoels and planarians will reveal the evolution of GRNs over 550 million years of evolution. Wnt signaling, which has a conserved role in correctly specifying tissue identity along the anterior-posterior axis in Hofstenia and Schmidtea, will serve as an anchor-point for a systems-level approach to identify upstream and downstream GRNs. Wound-induced gene networks that control the Wnt pathway will be identified by transcriptome profiling and RNAi. Assays for open chromatin will be used to identify enhancers and direct transcriptional regulators of Wnt pathway components. RNAseq and candidate gene approaches will be used to identify downstream gene networks controlled by Wnt signaling. Together, these experiments will reveal the regulatory mechanisms through which wound-induced gene networks control a putatively conserved module for patterning new tissue in two animal phyla.

National Science Foundation (NSF)
Division of Integrative Organismal Systems (IOS)
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Paul A. Krieg
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Harvard University
United States
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