A molecular mechanism enabling correct sperm motility has been uncovered, shedding light on a key cause of male infertility.
The mechanism, known as glycylation, modifies tubulin, a key component of structures called microtubules which form the sperm's tail, also called the flagellum. Researchers across Europe have found that without this modification, the action of the flagellum is altered, preventing sperm from moving in a straight line towards the oocyte.
'The core of the sperm flagellum is composed of microtubules, along with tens of thousands of tiny molecular motors, called dyneins, that make it possible to rhythmically bend these microtubules to produce waves for movement and steering' said Dr Sudarshan Gadadhar, lead author of the study, who is based at the Institut Curie in France. 'In the absence of glycylation, [the dyneins] became uncoordinated, and as a result, we suddenly saw sperm swimming in circles.'
The study, which appeared on the cover of Science, was conducted on a genetically modified line of mice which lacked Ttll3 and Ttll8, two enzymes essential for glycylation. The researchers then used cryo-electron microscopy, a new technique for looking at molecules on an atomic scale, to study the structure of the flagellum and the surrounding dyneins.
The researchers concluded that, whilst the flagella were correctly built, the lack of glycylation meant that the dynein molecules were not coordinated. This led to disordered beating of the flagellum, causing the sperm to move in circles.
The study may have a significant effect on how we think about reproductive health in humans, where 80 percent of infertility cases have been attributed to low sperm motility. As the paper states, 'considering that human sperm are more susceptible than mouse sperm to deficiencies in sperm motility, our findings imply that a perturbation of tubulin glycylation could underlie some forms of male infertility in humans.'
The authors also suggest that this discovery may have implications outside of reproductive health. This is because microtubules, which form the flagellum, are part of the cell's skeleton and fulfil a wide variety of functions.
'Our findings provide direct evidence that microtubules have an active role in regulating fundamental biological processes via a code of tubulin modifications' said Dr Gaia Pigino, from the Max Planck Institute of Molecular Cell Biology and Genetics in Germany, and Dr Luis Alvarez, from the Center of Advanced European Studies and Research in Germany, who led the study. 'Hence, our work opens a door to a deeper understanding of multiple diseases, such as developmental disorders, cancer, kidney diseases, or respiratory and vision disorders.'