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With Mice, Urine Powers Social Networking

Researchers are learning the secrets of mouse chemical communication by peering into their pee

by Sarah Everts
October 3, 2011 | A version of this story appeared in Volume 89, Issue 40

Wild Mice
Credit: Shutterstock
Learning the way mice communicate may help researchers control populations.
Credit: Shutterstock
Learning the way mice communicate may help researchers control populations.

Mice can’t post their relationship status and other personal details on a Facebook account for other mice to view, so the little rodents make up for their lack of Internet access by peeing a lot.

Manly Brew
This volatile molecule found in dominant male mouse urine helps get females in the mood for love.
Structure: 2-sec-Butyl-4,5-dihyrothiazole, a volatile molecule found in male mouse urine, helps get females in the mood for love.
This volatile molecule found in dominant male mouse urine helps get females in the mood for love.
Protein Punch
Credit: Jane Hurst
Major urinary proteins (MUPs) all adopt this β-barrel 3-D fold, which contains a cavity capable of holding volatile molecules.
Major urine protein structure.
Credit: Jane Hurst
Major urinary proteins (MUPs) all adopt this β-barrel 3-D fold, which contains a cavity capable of holding volatile molecules.

Urinating is not just a way for mice to flush out waste—it’s a full-on communication strategy.

Mouse urine contains all sorts of vital pieces of information that others in their community find fascinating, says Jane Hurst, a behavioral ecologist who studies chemical communication in mice at the University of Liverpool, in England.

These scent marks contain molecules that indicate sex, male dominance, pregnancy, or when a female is ovulating (and thus recruiting a little romance). In addition to these general status updates made from volatile small molecules, mouse urine also contains a cocktail of proteins whose relative concentrations are unique to different individuals, so that other mice know who exactly has left a liquid calling card, explains Robert J. Beynon, a protein chemist at the University of Liverpool who collaborates with Hurst, in addition to being her spouse.

“Mice leave urine scent marks on all surfaces” and spend a lot of time nosing around in the marks left by others, Hurst says. The information gained from urine seriously influences one mouse’s response to another, such as whether he—or she—will even approach, be aggressive, or decide to mate with the other mouse.

Studying how mice orchestrate their social lives through chemical signaling goes beyond just interspecies voyeurism. If researchers learn to eavesdrop on mouse communication, they may be able to leave these rodents chemical messages that deter the animals from eating valuable provisions, particularly in developing nations where food security is often a major problem, Hurst says.

In addition to disrupting mouse communication to save food supplies, it may also be possible to use the chemical signaling to control mice in places like New Zealand, where indigenous bird populations evolved without rodent predators and are jeopardized because mice that arrived with British colonists are devouring eggs of endangered species.

For decades, behavioral ecologists have known that mice lubricate their social lives with urine. By the 1980s, researchers such as Milos Novotny at Indiana University, Bloomington, had begun to identify a variety of volatile chemicals in mouse urine, such as 2-sec-butyl-4,5-dihydrothiazole, which indicates a male mouse is dominant in the community.

Then in the 1990s researchers began taking a closer look at components of the urine that weren’t wafting off into the air but were remaining in the damp deposits. In particular, they looked at a potpourri of proteins found in mouse urine, which are aptly named major urinary proteins (MUPs).

Hurst and Beynon discovered that wild mice excrete some 12 to 15 different kinds of MUPs in their pee, all of which seem to adopt a similar three-dimensional barrel-shaped structure. The MUP protein barrel contains a cavity that can harbor volatile chemical signals.

By acting as containers for smelly molecules, MUP slows the release of the chemical signals into the air from the urine. It makes sense, Beynon says, that if mice are using the fragrant, volatile molecules as a form of social advertising, they don’t want the advertisement to disappear into the air after just a few minutes. “So instead mice encapsulate their advertisement inside a protein, and as a consequence they get release over hours instead of minutes,” he adds.

Besides the role of MUPs as slow-release capsules, Hurst and Beynon have found that the presence or absence of different MUPs in urine gives each mouse an individualized signature that helps mice recognize each other, as well as recognize whether a particular mouse is genetically related or not.

Because MUPs are not volatiles—they remain dissolved in urine—mice detect the protein signals using a specialized sensory apparatus in their nose called the vomeronasal organ, which complements the function of their other olfactory sensors. Mice are drawn to another mouse’s urine from the odors wafting off the pee. Then the mouse will actually stick its nose directly into the drying or dried urine scent mark, allowing its vomeronasal organ to additionally detect molecules suspended therein, Hurst explains.

Receptors in the mouse vomeronasal organ may recognize slight differences in the amino acid residues found on the outside of a MUP’s barrel structure, allowing mice to recognize the unique MUP cocktail of their family, lovers, and foes, Beynon says. But precisely how this occurs is still unknown.

Last year, Hurst and Beynon discovered yet another role for one of the MUPs found in male mouse urine. They found that one particular MUP has a potent role in mouse sex: It stimulates sexual attraction in female mice, and it also helps female mice memorize other components in the urine of that particular male. Hurst and Beynon decided to name this MUP darcin, after Mr. Darcy, the alluring male lead in Jane Austen’s “Pride and Prejudice.”

Despite its particularly potent role in mouse sex, darcin also has the same 3-D structure as the other MUPs and differs in amino acid sequence from other MUPs by only a handful of residues. Other experiments are showing that darcin “stands out from the other MUPs due to its protein chemistry properties,” Beynon says. For example, despite being so similar to other MUPs, darcin runs much faster than its siblings on a protein gel. Beynon and Hurst are trying to figure out what it is about this protein that elicits its magical attraction for females and whether other MUPs have specialized communication roles.

“It’s all really wonderful work,” comments Robert T. Mason, a chemical ecologist at Oregon State University. Hurst and Beynon’s MUP work sets the stage for understanding many aspects of mouse social behavior that researchers have long observed but have been unable to explain at a molecular level, Mason adds, such as the onset of fertility in female mice in the presence of a new male or the coordination of fertility cycles among female mice that cohabitate.

One of the challenges to Hurst’s studies is the fact that she chooses to work with wild mice, as opposed to the typical research mice found in laboratories around the world. Wild mice are much more aggressive than lab mice, but Hurst says decades of inbreeding make lab mice poor proxies for their feral counterparts.

“Lab mice have been bred for 300 to 400 generations on the basis of two selection criteria,” Beynon adds. “One is that they don’t bite the technician, and the other is that they happily have sex with their siblings.” The inbreeding reduces MUP diversity so that the urine cocktail of lab mice contains about half the number of MUPs as that of wild mice, Beynon says. So the team members work exclusively with wild mice and use mass spectrometry and proteomics to study the protein chemistry of MUPs in the urine samples they collect.

Next up, they hope to investigate how other animals use secretions to secure a little romance. The goal is to understand how different animals achieve with excreted molecules what humans orchestrate with a snappy pickup line—or perhaps with an as-yet-undiscovered human pheromone.


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