Unknown cause of male infertility identified.

A new cause of male infertility has been identified that induces sperm to swim in a circular pattern. Subsequently, the sperm are unable to swim in a straight line to reach the female egg, meaning the male is unable to reproduce, rendering them infertile.

Male infertility is a common condition that affects around seven percent of all men globally. Specifically, this condition means a male is unable to cause a pregnancy in a fertile female and is usually caused by abnormal sperm function or production. In spite of its widespread prevalence male infertility has been deemed a complex condition further complicated by a lack of treatments specifically targetting these sperm deficiencies.

Cilia and flagella are antenna-like structures that protrude from most of the cells in our body. An example of flagella is the sperm tail, which is essential for male fertility and sexual reproduction. To enable conception the sperm tail or flagellum must beat in a very precise and coordinated manner to allow the sperm to swim in the correct direction. Accordingly, failure to do so can lead to male infertility.

A new cause of male infertility

Now, a study from researchers led by the Institut Curie identifies a specific reaction that must occur within the sperm structure which is essential to keep it swimming in a straight line. The team explains if sperm is unable to swim in a straight line it is unable to meet and fertilize the female egg, providing a previously unknown cause of male infertility. The study is published in the journal Science.

Previous studies show that one essential component of every eukaryotic cell is the cytoskeleton, the organic foundation of a cell. The cytoskeleton is made up of microtubules, tiny tubes consisting of a protein called tubulin, which is structurally similar across most organisms. Moreover, modifications of the microtubule cytoskeleton have emerged as key regulators of cellular functions and a growing number of human pathologies, including the quality of sperm.

In the same way, the sperm tail is composed of microtubules along with tens of thousands of tiny molecular motors called dyneins. Dynein protein ‘motors’ rhythmically bend the microtubules to produce waves for movement and steering. Sort of like a timed injection of fuel, the regimented coordination of these motors in the tails of sperm is crucial for movement. This is because the speed and direction of sperm are key for sexual reproduction, and therefore, male fertility.

To date, it has been suggested that enzymatic modification to the tubulin making up individual microtubules regulates specific functions within living cells. The modification, known as tubulin glycylation, is found exclusively in cilia and flagella. Thus, it is theorized that glycylation may be essential in functional cilia and flagella, however, its role in the form and operation of these organelles remains unclear. The current study demonstrates in mice that in the absence of tubulin glycylation sperm swim around in circles, resulting in a reduction in male fertility.

How sperm swims in a straight line

The present trial generates a mouse model that lacks the ability to perform tubulin glycylation in the cell cytoskeleton. Results show that even though the lack of glycylation in flagella does not cause any abnormalities in the sperm flagellum structurally, the sperm is unable to swim in a straight line. This suggests that although tubulin glycylation is nonessential for the formation of cilia and flagella, it is imperative for the rhythmic coordination of the sperm flagellum. As a consequence the sperm cannot swim in a straight line, interfering with their ability to reach the female ovum. 

To investigate why the lack of glycylation causes sperm to swim around in circles the team used cryo-electron microscopy to visualize the microtubules and dynein motors making up the sperm’s flagellum. The analysis revealed the lack of glycylation disrupts the swimming of the sperm by interfering with the coordinated activity of the dynein motors.

A new target crucial for male fertility

This group states their study shows how important glycylation is in controlling the uniform beat of flagella via the regulation of dynein motors. This is turn causes the ‘incoordination’ of flagella, and by extension male infertility. They go on to add as human sperm are more susceptible than mouse sperm to deficiencies in sperm motility, the findings indicate any disruption of tubulin glycylation could underlie some forms of male infertility in humans.

The team surmises they have uncovered a mechanism that controls flagella function, the direction sperm swims, and, by extension, male fertility. For the future, the researchers state their data provides more clarity for diseases linked to the malfunction of cilia, such as cancer, kidney disease, vision disorders, and respiratory conditions.

Source: Max-Planck-Gesellschaft

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