July 1, 2013 | 5
Sometimes, funny stories really bring out the wonder of the human body. You can get orgasms triggered in your feet, because of overlap in the sensory cortex. Receptors that are involved in narcolepsy are also involved in how much you eat. And knocking out receptors that regulate taste…can make you sterile? Who knew?
(Figure 2A from the paper)
Mosinger et al. “Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility” PNAS, 2013.
Let’s start with taste. We taste because the chemicals in foods hit receptors on our tongues. Receptors for sweet, salt, bitter, sour, and umami (which can commonly be thought of as “savory”). Now, a receptor isn’t just a single protein, it’s actually several protein subunits working together to function. So, for example, the receptor subunit TAS1R3 is a subunit that can play two different tasting roles. When combined with one other subunit, it helps to sense sweet (like saccharin), and when combined with another, if helps you taste umami (like MSG, which is definitely umami flavored). If you get rid of the gene for TAS1R3, you end up with an animal that can’t detect either sweet or umami very well.
There’s another subunit that is covered in this paper as well, GNAT3. GNAT3, instead of being specific for something like sweet or bitter, instead plays a role in “basic taste“. But these two protein subunits are not JUST expressed on the tongue and in the gastrointestinal tract. They are expressed elsewhere in the body…and especially in the testicles.
But the role of the testes came about by accident. At first, the authors of the study were trying to study what happens when both TAS1R3 and GNAT3 are absent. They made knockout mice for each of the two genes and tries to breed the mice together to get animals that were knockedout for both genes. But…those mice were very hard to come by. You could get each knockout separately, but double knockouts for both TAS1R3 and GNAT3 just were not born.
But not all double knockouts. It turns out that female double knockouts, without both TAS1R3 and GNAT3, were born just fine. What was happening?
So here’s the issue: male mice without GNAT3 breed fine. Male mice without TAS1R3 breed fine. Females without GNAT3 or TAS1R3, or even lacking both, breed fine. But males without GNAT3 and TAS1R3 aren’t showing up. This suggests that something about GNAT3 and TAS1R3 together are required for normal production of males. And this means that what’s probably failing is the sperm.
How do you investigate this? If mice without both genes aren’t born, you have to make them. To do this, the authors made a mouse that was a double knockout for both GNAT3 and TAS1R3…but it HAD a HUMAN TAS1R3 instead. Since it still had a gene that was functioning for one of the two subunits, GNAT3 or TAS1R3, the males were born just fine. But the authors could then use drugs to block the humans TAS1R3 subunit (with the drug clofibrate), to see what happened to the mice when neither the GNAT3 or the TAS1R3 were working.
So the authors put clofibrate into the water of normal male mice, and mice that had the human TAS1R3 gene. Then they put the males in with females. All the males got busy, and the females paired with normal male mice got pregnant almost immediately. But the male mice with a knockout for GNAT3 and TAS1R3 with the human TAS1R3 blocked by the clofibrate were completely infertile. And if you got rid of the clofibrate? Their fertility came BACK.
Looking closer, the scientists saw that then GNAT3 and TAS1R3 were shut down or non-existant, the males showed major signs of testicular degeneration. The sperm couldn’t swim, and the testes themselves looked malformed. The two receptor subunits might be involved in taste…but they are also involved in testes! And where they are lacking, sperm cannot develop.
Above you can see Figure 2A. This is a normal mouse, and you’re looking inside the testis. Note the little lines in the middle? Those are sperm tails, with the heads pointing out. All is well here.
But above is Figure 2C-2F. These are mice that were knockouts for GNAT3 and mouse TAS1R3 with human TAS1R3, and then treated with clofibrate. The testes look weird. There are strange dark blotches and most importantly…no sperm tails.
Now you’ll notice that the knockouts of two proteins are required here. BOTH GNAT3 and TAS1R3 have to be gone to get infertility. Why? It’s tough to say, but it could be that the two subunits link up to similar pathways inside the cell (in this case cAMP). This means that, if they signal in similar ways, the loss of one protein may be ok. Without GNAT3 for example, TAS1R3, signaling via a similar pathway, may be able to make up the difference, and vice versa. But if both proteins are gone, the pathway is lost, and in this case, so is fertility (not to mention a good sense of taste!).
To me, this paper emphasizes the fantastic complexity of our bodies. Our bodies can take a receptor in one place used for one thing (taste), and use for something entirely different elsewhere in the body (your sperm!).
But this is more important than just complexity. There are lots of things in our environments that bind to these receptors, especially TAS1R3. There are natural and synthetic sweeteners, as well as other things like herbicides which can bind to these receptors. This may mean that herbicides taste sweet, but it could also mean that the TAS1R3, when expressed in places like…the testes…may be affected by the presence of these sweeteners or herbicides. Of course, just knowing that the receptors bind these chemicals is no proof at all that the chemicals play a role in male infertility, that requires actually looking at those chemicals and their effects on sperm, which hasn’t been done (and would have to include moving from mice to humans, where the same receptor might not behave in quite the same way). But findings out that the TAS1R3 is present in sperm gives us new targets to look at when studying infertility causes.
And it also gives us new targets to look at when studying infertility treatments. After all, if these receptor subunits both play a role in sperm maturation, it’s possible that stimulating them could help in some types of male infertility. So this could be a new way to look at treatments for infertility, as well as a new avenue to look at causes. And it’s an interesting story of why mouse sperm may stop swimming…they may have lost their “taste” for it.
Mosinger et al. “Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility” PNAS, 2013. DOI.