Genetic, epigenetic, and post-transcriptional basis of divergent tissue regenerative capacities among vertebrates

Regenerative capacity varies widely in the animal kingdom, with invertebrates like planarians capable of regenerating entire organisms. Within vertebrates, phylogenetically primitive organisms such as zebrafish and urodele amphibians can regenerate limbs, spinal cords, and hearts, while adult mammals are largely limited to regenerating specific tissues. This review examines the regenerative capacities of appendages, spinal cords, and hearts in model organisms like zebrafish, axolotl salamanders, frogs, and mice, highlighting genetic and epigenetic commonalities across vertebrate species and addressing theories for the decline in regenerative capacity during evolution. Despite divergent tissue regeneration capacities across the animal kingdom, there are commonalities among appendage, heart, and spinal cord regeneration in fish, amphibians, and mammals. Regeneration is generally nerve-dependent and governed by conserved genetic, epigenetic, and post-transcriptional machinery.

• 1
  Nerves play a crucial role in organ regeneration across diverse species, influencing progenitor cell proliferation and differentiation through the production of promoting factors, suggesting an evolutionarily conserved role of nerves in regeneration across vertebrates.
• 2
  Regulatory enhancers, like the lepb-linked regeneration enhancer (LEN) in zebrafish, direct regeneration-specific gene expression and may explain variance in regenerative capacity, with potential for reactivation in mammals despite evolutionary loss.
• 3
  Epigenetic modifications, including histone demethylation and methylation, regulate gene accessibility and play a critical role in regenerative processes, with modifications capable of both stimulating and stymying regeneration.