Molecular and cellular mechanisms underlying the nerve dependence of regeneration

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PROJECT SUMMARY Cells are the building blocks of life. The functions of tissues and organs emerge from the dynamic properties and interactions of cell types. The diversity of cell types and cellular states, over time scales ranging from minutes to millennia, underlies the anatomical and physiological diversity of animals. Because cellular diversity is ultimately the result of differential gene expression, studying organismal biology from a cell type perspective is necessary to link genes to animal physiology and pathology. The overarching goal of our research program is to understand how the molecular diversity and evolution of cell types determines how vertebrate species adapt differently to changes in their environment. We focus on problems where the evolutionary perspective has the potential to reveal fundamental principles that may generalize across species. A smaller part of the lab investigates the relationships between cell type evolution and the evolution of behavior. The majority of the lab focuses on regeneration, to elucidate how dynamic interactions of cell types in space and time result in the regeneration of complex tissues and body parts, with an emphasis on those cell types and interactions that might be conserved across body parts and species. Our goal for the next five years is to lay the foundations of this research program. Specifically, we propose to develop further the Spanish ribbed newt Pleurodeles waltl as a model for regeneration. Urodele amphibians such as newts are the terrestrial vertebrates with the highest regenerative capacity. Pleurodeles is an excellent complement to axolotl, the most popular amphibian model for regeneration: (i) these two species diverged about 150 million years ago, and their comparison may reveal fundamental principles of regeneration; (ii) unlike axolotl, Pleurodeles has a complete life cycle, including metamorphosis into a true adult stage; (iii) Pleurodeles has a sequenced genome and established methods for transgenesis and genome editing. To maximize the impact of our research and discover evolutionarily conserved mechanisms, we will focus on the nerve dependence of regeneration, a phenomenon observed in almost every highly-regenerative species and in a variety of tissues. Specifically, we will compare brain and limb regeneration. First, we will determine whether regeneration depends on the same neural secreted proteins in these two different contexts. Second, we will clarify whether neural activity is necessary to mediate the effects of nerves on regeneration. Third, we will decipher how neural signals induce the proliferation of stem or progenitor cells. Impact: this work will reveal molecular and cellular mechanisms of regeneration that generalize across body parts, and lay the foundation for comparative studies across species. The discovery of general mechanisms underlying regeneration will clarify why many species, including humans, have lost regenerative capacity, and may catalyze the development of new approaches for human regenerative medicine.