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.