How the Mouse Got Its Stripes

In The Second Jungle Book, Rudyard Kipling tells the story of the first tiger, who killed a buck during a time of peace. As punishment, the first elephant commanded the jungle’s trees and creepers to mark the tiger, “drawing their fingers across his back, his flank, his forehead, and his jowl.” Hence: stripes.

That fanciful tale was a predecessor to Kipling’s later Just So Stories for Little Children, and it’s one of many folk tales explaining why tigers are striped, or why zebras are striped, or why leopards are spotted.  Mammalian coats, after all, are conspicuous, beautiful, and charismatic. They demand explanation. And yet, we know very little about their actual origins, about the genes and molecules that produce these striking patterns. That’s largely because the mammal that scientists do the most experimental work upon—the laboratory mouse—is not striped.

But #notallmice. Southern Africa is home to the striped mouse, which, as its name suggests, has stripes—four black ones and two light ones running down its back. By studying this adorable creature, and its North American cousin, the chipmunk, Ricardo Mallarino from Harvard University has discovered a critical and surprising gene that paints their backs.

That not only gives us a more realistic version of Kipling’s tales, but also speaks to one of the most important evolutionary issues of all—how genetic changes lead to physical changes, how DNA sculpts bodies.

Mallarino showed that even before the mice are born, their stripes are already set. Dark and light bands appeared on their gray embryonic skin, and over a thousand genes were more active in one of these regions than the other. Some were more active in the dark stripes and were known to be involved in making dark pigments—so far, so obvious. But another gene, known as Alx3, was almost seven times more active in the light stripes than the dark ones—and that was a surprise.

“I’ve been studying pigmentation for 15 years, and I’ve never heard of this gene being involved,” says Hopi Hoekstra, who led the study. It’s not like Alx3 is a new gene, either. Other scientists have studied it extensively, showing that it helps to sculpt the heads and faces of mice, and that mutant versions can lead to cleft palates. And yet, in all those experiments, no one had noticed any differences in color. “But many of those studies had been done in a strain of albino mice,” says Hoekstra. “Once we pieced that together, it all made sense.”

By using several techniques to switch Alx3 on or off, the team showed that it works by suppressing another gene called Mitf. In doing so, it stops the development of melanocytes—the cells in the skin that produce dark pigments. That’s what lightens the mouse’s fur, creating light stripes amid the dark ones.

The same thing happens in chipmunks. Striped mice and chipmunks look very similar but the latter is a type of squirrel, and separated from the mice by around 70 million years of evolution. It seems that all rodents use Alx3 to create light fur on their flanks and bellies, but these two groups have independently recruited the gene to also make light stripes on their backs.

What about other mammals? There are a lot of striped rodents that vary in the thickness and number of their stripes, from single-striped grass mice to thirteen-lined ground squirrels. It’s easy to imagine that by tweaking where Alx3 is active, you can get a wide diversity of patterns. Mallarino’s team even got their hands on skin from a zebra, and found some signs that Alx3 is more active in its white stripes than its dark ones. “We had a sample size of one, though,” says Hoekstra, “but it’s certainly possible that this is also involved in more diverse stripe patterns.”

That’s not to say that Alx3 is the only game in town. In 2012, another team showed that two different genes—Taqpep and Edn3—control the coat patterns of cats, from cheetahs to tabbies. These genes also act in a different way: while Alx3 affects how melanocytes mature, Taqpep and Edn3 prompt the same melanocytes to switch from making light pigments to dark ones.

Both the mouse and cat stories end on a cliffhanger. Neither explains why genes like Alx3 and Edn3 are active in some parts of the skin and not others in the first place. “In other words, how did the stripes themselves develop and evolve, as opposed to the light and dark colors within them?” asks Trisha Wittkopp from the University of Michigan. “That is the million-dollar question and we don’t know,” says Hoekstra, who is actively looking into it.

One possibility was suggested by the legendary code-breaker Alan Turing back in 1952. He argued that animal patterns are produced by two molecules that diffuse throughout the skin and vie for dominance. Depending on how fast they travel and how strongly the interact, they can create landscapes that range from spots to stripes to blotches. (You can try it for yourself in this Java applet.) There’s growing evidence that these Turing patterns exist in animal skins, especially in fish. But Hoekstra isn’t convinced that they apply to her mice.  “There’s not an obvious connection,” she says.

Time will tell if she’s right. Indeed, these kinds of studies, which look for the genes behind obvious physical traits, are easier than they have ever been. Scientists can now study animals outside the classic mice, flies, and worms—the so-called “model organisms”—that have dominated laboratory science for decades.

“We’re now at a time where the developmental basis of color patterns can be investigated in any species that can be easily reared in the lab,” says Antonia Monteiro from the National University of Singapore. Next-generation sequencing technology can tell you which genes are active in different parts of the body, and other tools can show you what happens when those genes are switched on or off. Gene-editing techniques like CRISPR will only make such experiments even easier. The results will be stories that are less fanciful than Kipling’s, but no less fascinating.