How do sperm find their way to the egg before fertilization? Heaven knows that from the sperm's perspective this is not a trivial question, as finding the egg is like looking for a needle in a haystack. To successfully locate the egg, sperm have to possess some navigation system. In metazoan organisms,sperm navigate by chemotaxis, moving along a concentration gradient of an attractant released by the egg.
In 1992, a large mammalian gene family was described that encodes approximately 1000 different odorant receptors, mostly expressed in the cilia of olfactory receptor neurons. However, several distinct odorant receptors have also been found to be expressed either predominantly or exclusively in sperm flagella. Since the flagellum provides the propulsive force for sperm locomotion, it was speculated that these testicular odorant receptors are directly involved in navigating the sperm towards the egg. In a recent Science paper, Marc Spehr and his colleagues investigated a previously undescribed testicular odorant receptor, termed hOR17-4, in order to uncover its role in human sperm physiology. By combining molecular biology,pharmacological studies and behavioral assays, they were able to demonstrate for the first time that a testicular odorant receptor directly functions in sperm chemotaxis.
First, the scientists decided to test which odors the receptor `smelled'. They expressed the recombinant receptor protein in human embryonic kidney cells, treated the cells with a complex mixture of odorants and measured the receptor-induced calcium release. By subdividing the mixture into smaller fractions, they were able to identify the active ligand. They also tested the cells' responses to related substances and found that a broad spectrum of substances, including bourgeonal, activated the receptor.
After finding active odorants, Hans Hatt's team wanted to see how their receptor functioned in live human sperm. They tested whether the identified ligands could induce a calcium response to odorant molecules in sperm by measuring cytosolic calcium levels in the cells. The sperm responded to bourgeonal and other active ligands but with a significantly higher sensitivity then when the receptor was expressed in the kidney cells.
They also confirmed chemotactile behavior of human sperm, by tracing sperm locomotion in microcapillaries loaded with different bourgeonal gradients. The results of these locomotion assays clearly demonstrated that the sperm were navigating up the gradient, towards the area of highest bourgeonal concentration.
In summary, the outlined experiments suggest that hOR17-4 may be a crucial component in the fertilization process as it may be directly involved in helping the sperm navigate towards the egg. Although the follicular factors that attract mammalian sperm are not yet known, identification of a receptor that mediates sperm chemotaxis in vitro may pave the way to ascertain their molecular identity, which could help in the development of new therapies to help childless couples. It is also hoped that perturbation of hOR17-4-mediated navigation may lead to the development of new contraceptives with fewer adverse reactions than the current generation of contraceptives.
