Researchers discover key to axolotl’s regenerative abilities

The axolotl, a small salamander, possesses an extraordinary ability to regenerate almost any part of its body, captivating scientists for years due to its potential applications in human wound healing. Stanford Medicine researchers have now made a significant breakthrough by uncovering the secret behind this remarkable capability. They found that axolotls have an extremely sensitive form of the mTOR molecule, which regulates production.

Additionally, axolotl store messenger RNA containing genetic instructions for protein synthesis, enabling them to swiftly produce the necessary proteins for tissue regeneration after an injury. This discovery, published in Nature on July 26, opens up new possibilities for enhancing regenerative potential in humans by manipulating the mTOR pathway.

From mRNA to protein

In the past, researchers focused on studying changes in mRNA molecules after axolotl injuries to understand their regenerative potential. However, this approach only provided limited insights into protein production. Maria Barna's lab adopted a new strategy, examining which mRNA molecules were attached to ribosomes near the wound to identify the proteins being produced. Surprisingly, they discovered that when an axolotl loses a limb, it increases protein synthesis despite the energy cost. Further experiments revealed that axolotl cells store mRNA, translating only a small portion at a time. During regeneration, protein synthesis is activated, allowing the translation of numerous stockpiled transcripts and explaining the swift tissue repair. This unexpected role of protein synthesis emerged as the key to unlocking the mystery of the axolotl's remarkable regenerative abilities.

Protein synthesis activation on injury in axolotls but not in mice. Credit: Nature (2023). DOI: 10.1038/s41586-023-06365-1

A connection to mTOR

One question remained: What triggers the activation of mRNAs and their binding to ribosomes after axolotls lose body parts? The researchers noticed a shared sequence of nucleotides at one end of the stockpiled mRNA molecules, known to be regulated by the enzyme mTOR to promote protein production.

Further investigations revealed that the axolotl mTOR protein is highly sensitive due to a genetic alteration unique to axolotls and related salamanders. Unlike in humans and mice, where mTOR activates only during nutrient surplus, in axolotls, the slight influx of loose nutrients after an injury is enough to activate the ultra-sensitive mTOR. This turns on cellular factories, initiating the production of new proteins to facilitate regeneration.

Blocking mTOR with a drug used in cancer treatment hindered the axolotls' ability to regrow limbs, indicating the crucial role of mTOR in regeneration. Interestingly, axolotl mTOR is hypersensitive to stimulation but not hyperactive like in many human cancers, potentially explaining their remarkable cancer resistance.

While more research is needed, understanding how mTOR controls mRNA translation could offer insights into wound healing and tissue regeneration in humans. This discovery opens up new possibilities for exploring the biology of translation and its connection to healing and regeneration.

Source: Stanford University

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