If you want to know how we evolved  hair and fingernails, ask a frog.

They are impartial judges, since  they do not have any of those things. I joke, but this is actually  something researchers are doing to understand how four-footed  animals evolved to live on land.

Because despite their lack of fabulous manes, amphibians do have evidence of that  transition hiding out in their DNA. And this can help us understand everything from  life on land to why humans have hair today. [♪ INTRO] Claws, hair, feathers, scales, and  even horns can be grouped together under the umbrella of cornified skin appendages . I know… that’s gross.

They’re all made of similar proteins and  they usually develop in similar ways. That said, they’re not for everybody. Take frogs for example.

Frogs: not typically associated with  luscious locks or impressive horns. And you probably don’t normally  think of them as having claws either. But some species do have claws,  like the, western clawed frog, a favorite experimental model for  developmental biologists everywhere. They don’t have, like, a ton of claws.

There're three on each hind foot! But they are there. And claws don’t come up often  in the world of amphibians.

Plus, these claws grow differently than  claws found on other four-footed creatures. So these frogs’ toe-gear was thought to be  something they evolved totally separately. That meant non-frog claws must have made  their first appearance after the amniotes, which today includes the mammals,  the reptiles, and the birds, split off from the amphibian ancestors.

Or so we thought. But in a 2024 paper in Nature Communications,  researchers challenged that idea, and the consequences are  surprisingly long-reaching. They were studying keratins, the proteins  that make up cornified skin appendages.

God, I hate that. And they reached the conclusion that frog  claws share an origin with those of amniotes. In humans and the other amniotes, the expression  of keratin is overseen by specific genes.

Namely, the Hoxc13 gene. Hoxc13 belongs to a group called  Hox genes, short for homeobox genes. These are the master blueprints of a  developing organism, directing what happens where as a blob of cells turns into an embryo  with limbs and organs and all that good stuff.

They can do this because Hox genes code for  specialized proteins called transcription factors. And transcription factors essentially  turn specific genes on or off, so that the right functions are showing  up in the right place at the right time and you don’t grow hair in your kidney. They’re a little like the  middle management of the genome.

Their one job is to boss around  all the genes under them. And Hoxc13 has been put in charge of whether  or not we grow nails, hair, and the like. Now, there’s a funny quirk of Hox genes,  which is that each group of them is laid out on the chromosome in the same order that  they work in the body, from head to toe.

That means where a gene falls in its cluster  gives some clue as to where it does its work. You can expect a Hox gene with a name  ending in 1 to be involved near the head, going all the way up to 13  which happens at the tail end. And we literally mean the tail.

Hoxc13 is active in the tail fin  of ray-finned fish, for example. But as ancient fish continued to  evolve, Hoxc13 came to be turned on not just at the tip of the tail, but also  the tips of the fins of lobe-finned fish. Those fins would give rise to the  limbs of all four-footed animals.

Which means Hoxc13 is the director  of the film we are about to see. This SciShow video is supported  by Giving What We Can! An organization that works with experts to help you find and donate to the charities that can do the most good per dollar donated.

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To join a community making an impact on global problems, no matter your career, explore taking a pledge to give at givingwhatwecan.org/scishow In that 2024 paper, the researchers  showed that in clawed frogs, keratin genes are regulated by Hoxc13  – same as they are in amniotes. This led them to look for Hoxc13-regulated  keratin in other amphibians, and they also found some in everyone’s  favorite forever-baby, axolotls! And I know, It’s also pronounced  “asholot”, but look… I am who I am.

While axolotls don’t have actual claws, they do have brownish layers  at the tips of their toes. And sure enough, it was discovered these  were made of Hoxc13-regulated keratin too. This research revealed that there  was a shared evolution of claws long before amphibians and amniotes  made their evolutionary split.

And that might reveal how important keratin  was in transitioning to life on land. Instead of being a later innovation,  it was there the whole time. It seems likely that keratin structures  first evolved as a means of protecting those vulnerable tippy toes while also helping  with movement, and eventually prey capture.

From there, keratin took off to take  on a bunch of other important roles, like covering mammals in fuzz. That said, we’re still doing a lot of head  scratching around the relationship between these early origins of claws, and  our magnificent haircuts today. Given that Hox genes have such a thing for order, it’s not clear how Hoxc13 would  have gone from just making claws, like at the tips of limbs, to regulating  hair growth throughout a mammal’s body.

Because remember, they don’t wanna be everywhere. That’s other Hox genes’ turf. It’s possible Hoxc13 genes  were put to work in new places thanks to a type of genetic  sequence called enhancers.

Briefly, enhancers can help turn on genes,  including those for transcription factors, like your manager’s manager. And researchers have identified enhancers  that help boost expression of Hoxc13. But we don’t know the whole picture yet.

There were likely some intermediate evolutionary  stages as keratins took on new functions, but exactly what that looked  like, we just don’t know. Plus, those same enhancers  weren’t found outside of mammals, so this doesn’t explain how other amniotes  got their specialized skin coverings. It’s especially puzzling  in terms of bird feathers, which might have evolved separately  from other cornified skin appendages.

Oh my God, I want to stop  saying it so bad… cornified?! Their keratin proteins are  different from those found in hair. So we also still don’t know the full  role of Hoxc13 in bird evolution.

What’s clear, though, is that  keratins, especially claws, were there for us all the way through our  rocky, precarious transition to life on land. It’s nice to know they’ve had our backs  – or, our toes, at least – all this time. [♪ OUTRO]