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How An Ultra-sensitive On-off Switch Helps Axolotls Regrow Limbs

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, Ph.D., 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."

More information: Olena Zhulyn et al, Evolutionarily divergent mTOR remodels translatome for tissue regeneration, Nature (2023). DOI: 10.1038/s41586-023-06365-1

Salamanders' regenerative potential might be driven by a specific protein variant, Nature (2023). DOI: 10.1038/d41586-023-02111-9

Citation: How an ultra-sensitive on-off switch helps axolotls regrow limbs (2023, July 31) retrieved 6 August 2023 from https://phys.Org/news/2023-07-ultra-sensitive-on-off-axolotls-regrow-limbs.Html

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14 Pink Animals That Wow And Woo

From bright fuchsia sunsets to ballet-slipper blooms, Mother Nature seems to have a soft spot for pink. And the rosy displays don't just stop with astronomical events and flowers. All manner of creatures boast various shades of magenta, fuchsia, coral, and rose. Case in point? Consider these blushing beauties.

Roseate Spoonbill Arthur Morris / Getty Images While flamingos may be the poster children for pink animals, we couldn't pass up the beautifully quirky roseate spoonbill, a gorgeous pink wading bird with a charming spatulate bill. The color of the spoonbill results from its diet of crabs and shrimp. Sadly for these exquisite creatures, their pink primary feathers were highly prized for use in ladies' fans in the late 19th century; by the 1930s, the once healthy Florida population had dipped to a total of only 30 to 40 breeding pairs. Fortunately, full legal protection against hunting was enacted, and there are now over 1,000 nesting pairs in Florida. Pink Katydid Hans Neleman / Getty Images First described in 1874, pink katydids have inspired more than a century of discussion over the hows and whys of their incredible hue. At the turn of the 20th century, Harvard entomologist Hubbard Scudder suggested that the pink coloring could be seasonal and that green insects changed their colors with the autumn leaves for protection. American entomologist and myrmecologist William Morton Wheeler rejected this theory. Based on finding bright pink katydid nymphs in the prairies of Wisconsin and Illinois during July 1907, he suggested a genetic root to the condition. Wheeler compared the state to albinism. For the first time, pink katydids became recognized as genetic "mutants" in the scientific literature. Entomologists now believe they've confirmed that Wheeler was right. Whatever the reason, we're quite happy that there are such things as pink katydids in the world. Bargibant's Pygmy Seahorse Glen MacLarty / Flickr / CC BY 2.0 Talk about blending in. Bargibant's seahorse (or pygmy seahorse) lives exclusively on fan corals and are such masters of disguise (hence their lovely hues that match the pink of the coral) that they went unnoticed until a researcher found one while studying coral in a lab. The nodules on the seahorse even match the buds on the coral. They comes from the family Syngnathidae and measure a mere 1/2 to 1 inch in length. Web-Footed Gecko fotoclick / Getty Images

Web-footed geckos can thank their strangely translucent, salmon-colored skin for hiding them so well against the reddish sands of the Namib Desert where they live. Additional defense mechanisms include a vocabulary of clicks, squeaks, croaks, and other sounds to scare off potential attackers. Not to mention the old "break off the tail" trick that all geckos have.

But perhaps the strangest thing about this reptile is that it does not have eyelids and thus must lick its eyeballs to keep them moist, proving that the animal world is stranger (and even more enjoyable) than fiction.

Orchid Mantis Nurul Faridah / EyeEm / Getty Images In 1879, Australian journalist James Hingsley returned from Indonesia with stories of a carnivorous pink orchid that lured butterflies to its petals and ate them alive. As you may have guessed, it wasn't a flower he saw; it was the amazingly deceptive flower-mimicking insect Hymenopus coronatus — the orchid mantis. In a more recent study to determine if the orchid mantis' fancy disguise lured insects to their deaths, scientists were surprised to find that the mantises attracted more insects than real flowers did. And while other animals may camouflage with flowers to hide among and then ambush their prey, the schemes of the orchid mantis are different. They sit out alone on branches or leaves and pose as flowers rather than hiding amongst them. Nothing says "nature is intense" like hot-pink bug-eating flower bugs. Domestic Pigs Manop Boonpeng / EyeEm / Getty Images Some domestic pigs are black because they overproduce the pigment eumelanin, while pink pigs don't make any melanin at all and end up a "default" pink. But here's what's fascinating: Pigs evolved compelling coat colors only after domestication because of a human penchant for novelty, according to a study looking at wild and domestic pigs. As it turns out, pink pigs would not have survived in the wild long enough—because they would be easily detected by predators—to allow for the pink-producing mutations to have occurred. Sea Stars Makri / Pixabay There are around 2,000 different species of sea stars, and they come in a range of colors, including pink, which help them camouflage or scare off predators. One can find sea stars living in oceans all over the planet, from tropical habitats to the cold seafloor. Marine scientists have adopted the challenging task of renaming these charming echinoderms "sea stars" instead of the once-common starfish. Elephant Hawkmoth Gale Hampshire / Flickr / CC BY 2.0 This pink and olive green moth—which has the unusual distinction of being named after a mammal, a bird, and an insect—is one of 1,400 species of hawk moths found across the globe. The colors help them attract a mate in the dark, and during the day, they hide among the bright pinks of the blossoms on their favorite foods: willowherbs and fuchsias. Hawkmoths are the only moths able to hover in front of flowers to feed, like hummingbirds do, and are among the planet's fastest flying insects, reaching speeds of up to 12 miles per hour. Amazon River Dolphin chem7 / Flickr The Amazon river dolphin—also known as the boutu, boto, or bufeo—has the distinction of being the largest of the freshwater dolphins, and happens to turn pink as it ages. In 2018, IUCN listed Amazon river dolphins as endangered. Primary threats include the use of them for fish bait, fishing with explosives, and contamination of the river water by mining operations. Axolotl Argument / Getty Images And here, the most charming salamander in all of the salamander world, the pink Axolotl (Ambystoma mexicanum), also known as the Mexican walking fish. They do come in other colors such as white, black, yellow, and green. White axolotls always have pink fringed gills; black axolotls have gills of blue. Not only are these amphibians just ridiculously cute, but they never undergo metamorphosis and thus stay in larval form their entire lives. Plus, they have super healing powers that allow them to do things like regenerate limbs. Sea Anemone Jayme Godwin / EyeEm / Getty Images Named after the terrestrial flower that is equally showy, the sea anemone comes in a rainbow of dazzling colors, pink being among the loveliest. The color of the sea anemone depends on where they call home. If their host is a coral or sponge, they tend toward vibrant. In a more drab environment like a rock, muted colors reign. But this creature that's related to coral and jellyfish is more than just a pretty flowery glob; the anemone has some surprising traits. For example, they are carnivorous, can live to be 50 years old, and some of them can grow as large as 6 feet in width. Pink Hairy Squat Lobster Subaluna / Shutterstock Part Dr. Seuss, part arachnophobe's nightmare, this beguiling marine crustacean known as the "pink hairy squat lobster" (Lauriea siagiani) is not a lobster at all. Also called a fairy crab, the "lobster" belongs to the group of crabs called Anomurans and is just a half-inch long. The pink color allows it to camouflage perfectly on the pink giant barrel sponges the squat lobster calls home. The pink hairy squat lobster can be seen in action in the following video. Nudibranch Reinhard Dirscherl / Getty Images The beautiful pink Tritoniopsis elegans, a marine gastropod mollusk that is often confused with sea slugs, first was scientifically discovered in the Red Sea. The range of this nudibranch spans the western Indo-Pacific. Of all the wildly beautiful traits that these creatures possess, their color is perhaps the most remarkable. Ranging in a spectrum from soft and dessert-colored to neon rainbow, they have evolved these hues for means of both camouflage—when matching their environment—and as a warning. Flamingo Photography by Marcio Ruiz / Getty Images We couldn't do a gallery of pink animals and not include the most famous pink creature of all. For our final blushing beauties, the epitome of pink: flamingos. Although when flamingoes first hatch, they are a drab grey; they develop into glorious shades of peach and coral primarily because of their diet. The red and blue-green algae they eat is chock-full of beta carotene, which contains a reddish-orange pigment, and the mollusks and crustaceans flamingos favor also possess pigment-rich carotenoids. And if their romantic color and heart-shaped kisses weren't lovey-dovey enough, consider this: Although flamingoes group in flocks that can number in the hundreds of thousands, a flamingo picks a single mate and generally remains monogamous for life.

Axolotl: The Adorable Amphibian That Can Regrow Its Body And Stay Looking Young Forever

an axolotl, or mexican salamander, looking at the camera with pink frills around its face

Name: Mexican salamander (Ambystoma mexicanum) also known as an axolotl

Where it lives: Lake Xochimilco and Lake Chalco, near Mexico City

What it eats: a variety of small invertebrates, along with some small fish

Why it's awesome: Despite its rarity, the axolotl's incredibly cute looks has made it one of the world's most famous amphibians, inspiring characters in Pokemon and Animal Crossing, making an appearance in Minecraft and even featuring as a Google Doodle.

With a happy little face and frilly gills, it's like the amphibian version of a puppy. This cuteness is caused by literally not growing up properly. Most salamanders undergo metamorphosis from their totally aquatic larval form to their mostly terrestrial adult forms. However, the axolotl is one of the salamander species that doesn't. Instead it retains all of its larval features — external gills and a fin along its back — and remains completely aquatic, but is able to reproduce. This is called paedomorphosis or neoteny.

Related: Meet the bizarre, grumpy-faced black rain frog that's terrible at jumping and swimming

It can also regenerate almost any part of its body, including its limbs, eyes and even parts of its brain, which makes it of great interest to scientists studying regenerative biology.

The axolotl is so beloved it is the national amphibian of Mexico and appeared on a 50 peso bill released in 2021.

Fish and Amphibians