Limb regeneration capacity varies among vertebrates, ranging from full regeneration in salamanders, to stage-restricted premetamorphic regeneration in frogs, to finger-tip regeneration in newborn mice and humans.The molecular and cellular basis for these differences in regeneration ability is not known and it is still unclear if these different regenerative events are tied by some common mechanisms with progressive restriction due to extracellular signals or cell intrinsic changes.Connective tissue fibroblasts or their progenitors play a key role in regenerating the patterned salamander limb. They harbor critical positional information and can reconstitute not only the connective tissue but also a complete, patterned skeleton. In contrast, such cells typically contribute to scar tissue during mammalian wound healing. Their role in mouse finger tip regeneration is unknown.I seek to determine the differences in fibroblast biology that account for the differences in regeneration between salamander, frog and mouse. To define the differences in composition of the connective tissue population, I will perform parallel lineage tracing of different fibroblast populations and their progenitors during wound healing and regeneration in salamander, frog and mouse. To determine differences in cell intrinsic potential versus extracellular cues required for regeneration I will perform cross-species transplantation of lineage-labeled cells between salamander and frog coupled with expression profiling to identify molecular changes that occur in cells in a regenerative versus non-regenerative context. Finally I will use this expression profiling and our molecular knowledge of limb regeneration factors to test whether frog and mouse cells can acquire regenerative traits at the cellular level by the forced exposure to intracellular and extracellular regeneration cues or by the downregulation of putative inhibitory factors.