https://scopeblog.stanford.edu/2023/07/26/how-an-ultra-sensitive-on-off-switch-helps-axolotls-regrow-limbs/ Skip to content Advanced features of this website require that you enable JavaScript in your browser. Thank you! Social Links Menu * About * Twitter * Facebook * LinkedIn * Instagram * FlipBoard Logo Left Content Stanford MedicineSCOPE Logo Logo Right Content Scope Stanford University School of Medicine blog Primary Menu Menu Search for: [ ] [Search] * Latest * Popular * Topics + Medical Research + Diseases + conditions + Medical Education + Global Health + Health Policy + AI, Technology & Innovation + Patient Care + Wellness * Search for: [ ] [Search] [AdobeStock_609749105-scaled-1152x578-1] [AdobeStock_609749105-scaled-1152x578-1] How an ultra-sensitive on-off switch helps axolotls regrow limbs Stanford Medicine researchers discover an "on-off" switch that powers tissue regeneration in axolotls, a type of salamander. Author Sarah C. P. WilliamsPublished on July 26, 2023July 26, 2023 It's one of the mysteries of nature: How does the axolotl, a small salamander, boast a superhero-like ability to regrow nearly any part of its body? For years, scientists have studied the amazing regenerative properties of the axolotl to inform wound healing in humans. Now, Stanford Medicine researchers have made a leap forward in understanding what sets the axolotl apart from other animals. Axolotls, they discovered, have an ultra-sensitive version of mTOR, a molecule that acts as an on-off switch for protein production. And, like survivalists who fill their basements with non-perishable food for hard times, axolotl cells stockpile messenger RNA molecules, which contain genetic instructions for producing proteins. The combination of an easily activated mTOR molecule and a repository of ready-to-use mRNAs means that after an injury, axolotl cells can quickly produce the proteins needed for tissue regeneration. The new findings were published July 26 in Nature. "Until now, it has been difficult to pinpoint a specific change in a single molecule in axolotls that was so critical for regenerative potential," said Maria Barna, an associate professor of genetics and the senior author of the paper. "We've made significant headway toward understanding how we may eventually manipulate the mTOR pathway to boost regenerative potential in humans." From mRNA to protein In the past, researchers trying to figure out how the axolotl regrows entire body parts -- including legs, tails, eyes and even the heart -- focused on how levels of mRNA molecules changed after an axolotl has an injury. Scientists have long used mRNA molecule levels as a proxy for protein levels; after all, mRNA must exist before a protein can be produced. However, these studies only shed light on what happens to the production of mRNA molecules after injury -- not what happens to the translation of mRNA into protein products. "There are hundreds of mRNA transcripts that appear after a wound, but researchers were really struggling to figure out what it was about salamanders that could explain their regenerative potential," Barna said. Her lab took a different approach, focusing on which mRNA molecules near a wound were attached to ribosomes, little molecular machines that create proteins. That helped the scientists zero in on which proteins were being made, rather than which mRNA molecules loitered near the injury site. Usually, when cells encounter stress (such as after an injury) they decrease overall protein production to save energy, so Barna's group expected to see fewer mRNA molecules bound to ribosomes. Instead, they saw more. "It was a 180-degree flip when we realized that when an axolotl loses a limb, it actually increases protein synthesis despite the energy cost," Barna said. Further experiments showed that axolotl cells 'stockpile' mRNA, translating less than 20% of it at any given time. When the researchers analyzed how axolotls respond to injury, they found that protein synthesis is activated, leading to the translation of hundreds of stockpiled transcripts. That long-term storage also explained the speed at which protein synthesis occurred during regeneration. "We had a gut feeling that looking at protein synthesis more closely would be important, " said Olena Zhulyn, PhD, postdoctoral scholar and lead author of the study. "But never in a million years did we expect that protein synthesis would be the key to the mystery of the axolotl's regeneration." A connection to mTOR A question remained: What was activating the mRNAs and causing them to bind to ribosomes after axolotls lose a body part? The researchers noticed that many of the stockpiled mRNA molecules had a shared sequence of nucleotides at one end of the mRNA which was known to be regulated by the enzyme mTOR to promote protein production. The research found that the axolotl mTOR protein is highly sensitive -- the axolotl variety contained a genetic alteration, an expansion in sequence, seen only in axolotl and related salamanders. Investigating further, Barna and her team collaborated with researchers at University of California, San Francisco to probe the structural differences between axolotl mTOR and mammalian mTOR. In humans and mice, mTOR (and resulting protein production) activates only when there's a surplus of nutrients. In other words, mammalian cells use mTOR to make proteins only in the best of times. But in axolotls, after an injury causes cell damage and the breakdown of many molecules, the small rush in loose nutrients is enough to flip the ultra-sensitive mTOR to its active state, turning on the cellular factories that make new proteins. "Finding this genetic change was a shock -- mTOR is an ancient enzyme that is the same in virtually all organisms," said Zhulyn. "But in axolotls we were seeing evolution of new sequences and a structure that changed its fundamental properties." When Barna and her colleagues blocked mTOR with a drug used to prevent protein production and cell division in cancers, the animals were no longer able to regrow limbs. The axolotl mTOR is hypersensitive to stimulation (in this case, injury) but is not more active than mammalian mTOR, they found. That's key, said Barna -- hyperactive mTOR has been linked to tumor growth in many human cancers. Given that the axolotl mTOR doesn't show hyperactivity, that could explain the remarkable cancer resistance seen in axolotls, she said. More research is needed to probe whether changing or stimulating mTOR in humans could improve wound healing or spur the regeneration of damaged, diseased organs, Barna said. "I think there are a still a lot of lessons to be learned about how this tight control of mRNA translation is allowing wound healing and tissue regeneration," said Barna. "There is a whole new world to be discovered when it comes to both the basic biology of translation and healing." Photo by Samantha * Share this article * Twitter * Facebook * LinkedIn * Flipboard * Email Category Cellular & Microbiology Medical Research Stanford Medicine Stanford School of Medicine Tags News Home4090 Related posts Category: Cellular & Microbiology It's a beautiful day in the intestinal neighborhood It's a beautiful day in the intestinal neighborhood Researchers have mapped the human intestine at the level of individual cells, showing how cellular neighborhoods work together in the gut. Author Hadley LeggettPublished on July 19, 2023July 19, 2023 Category: Alzheimer's Blood condition linked to protection against Alzheimer's Blood condition linked to protection against Alzheimer's Researchers at Stanford Medicine explore a potentially causative connection between a blood disorder and Alzheimer's. Author Christopher VaughanPublished on June 23, 2023June 26, 2023 Popular posts Category: Cellular & Microbiology How an ultra-sensitive on-off switch helps axolotls regrow limbs How an ultra-sensitive on-off switch helps axolotls regrow limbs Stanford Medicine researchers discover an "on-off" switch that powers tissue regeneration in axolotls, a type of salamander. Author Sarah C. P. WilliamsPublished on July 26, 2023July 26, 2023 Category: Addiction It's not 'just cannabis,' Stanford Medicine expert warns It's not 'just cannabis,' Stanford Medicine expert warns Stanford Medicine expert discusses the risks of cannabis addiction and how it impacts health, especially in young people. Author Mark ConleyPublished on July 12, 2023July 12, 2023 Footer Content Social Links Menu * About * Twitter * Facebook * LinkedIn * Instagram * FlipBoard Footer Bottom Widgets Archives Footer Middle Widgets Report Accessibility Issues Footer Middle Widgets * Terms of Use