Metabolic and transcriptional rewiring required for regeneration in Xenopus tropicalis

Abstract

Regeneration requires access to and mobilization of resources to build new tissues, which must then be patterned in order to restore the form and function of lost structures. This process begins at the time of injury, when a number of injury-induced signals initiate regeneration. Articulating how regeneration competent animals respond to injury to create a regeneration permissive environment, as well as instruct growth and patterning, is an important step in understanding the biology of complex tissue formation and in the advancement of regenerative medicine. I sought to identify post-wounding checkpoints using Xenopus tropicalis tadpoles, which are able to regenerate their tails following severe truncation. First, I define a regenerative refractory period that occurs during normal tadpole development in which regeneration is temporarily restricted. By showing that nutrient surplus at the time of injury dictates regenerative outcome, I identify nutrient sensing as a checkpoint in wound healing outcomes. I then examine how nutrients are mobilized to rapidly generate new tissue via glucose metabolism, characterizing a metabolic prioritization of the pentose phosphate pathway required for full regeneration. Finally, I explore how new tissues are properly patterned downstream of injury induced stressors by demonstrating a requirement for Hif1 in re-establishment of posterior patterning genes in tandem with Wnt signaling. This body of work delineates 3 key checkpoints (nutrient availability, metabolic prioritization, and stress-mediated transcriptional responses) which must be properly activated to allow regeneration and presents mechanisms for how each of these factors contributes to the regrowth of a tail.