Aquatic salamanders, or axolotls, are known for their mesmerizing ability to regenerate limbs lost due to injury or amputation. These gilled amphibians with glowing green skin gave scientists a major hint at how they regrow lost limbs.
According to senior study author James Monaghan, a professor of biology and director of the Institute for Chemical Imaging of Living Systems at Northeastern University, the cues behind whether to grow a whole arm or just the hand are a longstanding question. The presence of retinoic acid, found in retinol acne treatments, is responsible for signalling what part of the axolotl’s wounded cells should regenerate, and how.
Retinoic acid is also essential in human embryonic development, signaling where the cells are to grow into a head, and where to grow feet. However, for an unknown reason, most of our cells lose the ability to “listen” to the molecule’s regenerative cues while staying in the womb. Although regrowing entire human limbs is a distant dream, according to Monaghan, studying the signalling functions of retinoic acid in axolotls can help develop new gene therapies and human healing methods.
For the study, Monaghan’s team used genetically modified axolotls that gave a fluorescent green glow wherever the retinoic acid molecules were activated in the injured areas. Axolotls don’t glow in the dark naturally; genetic modifications help in recording the signalling cues of retinoic acid. At first, the scientists injected excessive amounts of retinoic acid into the salamander’s system. As a result, at the sites of amputation, they would grow entire arms instead of just the hand, leading to excessive growth beyond what was needed.
“We discovered that a single enzyme is responsible for breaking down retinoic acid in (axolotls’) bodies,” Monaghan said. When his team blocked this enzyme, the same excessive growth52 effects happened again. “This is really exciting and blew us away, as it shows that the levels of (natural) retinoic acid are controlled by their breakdown.” The enzyme called CYP26B1 blocks the regeneration mechanism from going into overdrive, preventing excessive growth. This regulatory mechanism signals whether to grow a hand or an entire arm. So far, Monaghan sees the relationship between retinoic acid and limb regeneration as one piece of the puzzle. The next step is to establish what genes are being targeted by retinoic acid molecules inside the cells to uncover the “blueprint” those cells follow.
When injured, axolotl cells undergo a process called dedifferentiation, in which they lose their “memory” and convert back to an embryonic state. In this stage, the cells become responsive to retinoic acid signals and start to grow again. In contrast, human cells don’t dedifferentiate. Instead, our tissues react to injuries by scarring and leaving heaps of collagen. Human limb generation is still far off, but studying the retinoic acid signalling pathway can lead to the development of technology that can help humans develop regeneration.
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