Evolutionarily divergent mTOR remodels translatome for tissue regeneration

Area of Science:

• Regenerative Biology
• Molecular Biology
• Comparative Physiology

Background:

• Mammals typically lack significant tissue regeneration capabilities, posing a biological mystery.
• The axolotl (Ambystoma mexicanum) is a model organism renowned for its remarkable regenerative abilities.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying axolotl limb regeneration.
• To investigate the role of protein synthesis and signaling pathways in regenerative versus non-regenerative responses to injury.

Main Methods:

• Polysome sequencing to analyze translational control of gene expression post-injury.
• Comparative analysis of injury response in axolotls and mice.
• Genetic engineering of axolotl mTOR (axmTOR) in human cells.
• Investigation of the mTORC1 pathway and nutrient sensing.

Main Results:

• Rapid activation of protein synthesis, specifically of transcripts encoding antioxidants and ribosome components, is crucial for axolotl limb regeneration.
• Protein synthesis is not significantly activated in mouse digit amputation models.
• The mTORC1 pathway is identified as a key regulator of regeneration and translation in axolotls.
• Axolotl mTOR exhibits unique sequence expansions, leading to a hypersensitive kinase primed for rapid activation.
• Inhibition of amino acid transport impairs axolotl tissue regeneration, highlighting nutrient sensitivity.

Conclusions:

• The translatome plays a critical, previously unappreciated role in orchestrating early wound healing during regeneration.
• Unique adaptations in the mTORC1 pathway contribute significantly to the regenerative potential observed in axolotls.
• Understanding these mechanisms offers insights into the broader potential for vertebrate regeneration.