Evolution is an aggressive recycler. Very few of a cell's signaling pathways are used just once. Instead, a signal that's interpreted in one way by a liver cell could be interpreted in a completely different way by an immune cell. One signaling pathway called Notch is used by so many different cell types (nerve, heart, blood vessels, immune cells, etc.) that scientists once quipped that there are only two types of biologists: those who work on Notch and those who don't realize they're working on Notch yet.

So it probably shouldn't be a complete shock to find that the signaling pathway that's involved in giving our tongues a sense of taste has been used for something completely different by other tissues. The surprise probably lies more in where they're used—in sperm during their maturation process. It's a finding that could have serious consequences for human fertility since there are both drugs and herbicides in use that inhibit the taste receptors.

This is probably one of the many discoveries that happened when researchers were trying to study something else entirely. That something was the process of sensing taste. Sweet and umami tastes are sensed by a complex formed from three related receptors called TAS1Rs. A complex of TAS1R2 and TAS1R3 senses sweet, while a 1 and 3 combination picks up the umami taste. Both of them signal through a protein called GNAT3. To study the process, some researchers were breeding mice to carry mutations in TAS1R3 and GNAT3.

It was easy to get mice that were mutant for one of their two copies of these genes. But when they bred them together, they couldn't get any animals that were mutant for both (i.e. lacking any functional copies of the TAS1R3 and GNAT3 genes). Normally when this happens, it's because the combination is lethal to the animals that carry it. But in this case, the problem wasn't that the embryos were dying. Instead, the male mice simply couldn't create sperm that carried both mutations.

To get around this, the authors did some clever genetics. The human version of TAS1R3 has several inhibitors that shut it down entirely; none of these work on the mouse version. So the authors inserted the human gene into mice and then used that to rescue the male sterility of the animals with both TAS1R3 and GNAT3 knocked out. Once the animals were adults, they could feed them the drugs and shut off the human receptor. They found the drugs made the males sterile, but stopping the treatment restored fertility within a matter of weeks.

What's going on in these drug-treated animals? It's a bit hard to tell, because most of the maturing sperm in them degenerate before they progress too far. The sperm that make it to maturity tend to be badly deformed. This does explain why the double mutation couldn't be inherited, though. At some point in their development, sperm need to get rid of one set of chromosomes so that only a single set gets passed on from each parent. If they got rid of the chromosomes that carried their working copies, the sperm would be left without a functional signaling pathway (which clearly means no healthy, mature sperm).

As of now, the authors can only speculate about what the receptor might be sensing (probably a sugar or amino acid, which is what the receptors normally recognize when acting in the tongue). And they have only an educated guess about how that signal gets translated into something that is essential to the health of the sperm. So these results leave plenty of things to keep grad students busy with.

In the meantime, the work has some obvious implications for human health. Several drugs that interfere with TAS1R3 activity are currently on the market to help modulate lipid metabolism. And a separate compound that blocks it is used as an herbicide. Last year, 55 million pounds of it were used in the US alone. With this paper, there are plenty of potential environmental influences that could be altering male fertility for the medical community to consider.

PNAS, 2013. DOI: 10.1073/pnas.1302827110 (About DOIs).

Listing image by Esther Simpson