In order for fertilization to take place, the sperm must get to the egg cell. They use the flagella, a thread-like cell extension in which various proteins work together so that the sperm can swim to the egg cell in a targeted manner, helps them move. If this interaction is disturbed, however, the sperm do not swim straight ahead, but in a circle. Researchers have now elucidated the exact mechanism of this disorder. According to this, certain proteins in the flagella, so-called microtubules, have to be modified in the right way so that the engine works optimally.
Microtubules are an important part of the cell skeleton. Although the tiny tubes made of tubulin proteins fulfill a multitude of different functions, their structure is very similar in most cells and organisms. In the scourge of sperm, in combination with motor proteins, so-called dyneins, they ensure that the germ cell can swim forward. The motor proteins move the microtubule threads in such a way that a serpentine rotary motion is created, which serves as a drive.
Appendage for correct function
A team led by Sudarshan Gadadhar from the Institut Curie in Paris has now proven that this drive is only fully functional if the microtubules have been modified in the right way for this task. Scientists had long suspected that modifications of the finished microtubules are necessary so that they can perform a specific function in different tissues. Earlier work had indicated that the so-called glycylation is important in the flagella of sperm. Other proteins that specialize in this process attach chains of the amino acid glycine to the microtubules. Only these appendages enable correct function, so the hypothesis.
To check this, Gadadhar and colleagues bred special mice that lack the proteins to attach the glycine chains. The microtubules in the sperm flagella of these mice were not glycylated. In fact, these mice were less fertile than genetically unmodified conspecifics. At first glance, the sperm appeared to be built correctly and were also able to swim. However, more detailed analyzes revealed that the movement was no longer purposefully straight ahead. Instead, the sperm swam in circles.
Motors out of step
According to Gadadhar, this observation can be explained by the fact that the activity of the motor proteins that move the microtubules must be precisely coordinated in order to generate exactly the right rhythm. But this is only possible if the microtubules are glycylated. “If the glycylation did not take place, the motor proteins did not coordinate with each other and we saw how the sperm suddenly swam in circles.” Although movements continued, these were not coordinated enough for a forward movement – like a rowing boat with the rowers off get out of step.
“This study shows how important glycylation is for controlling the flagellum’s dynein motors,” the authors summarize. “It is a prime example of how microtubule modifications directly influence the function of other proteins in cells. Our results provide direct evidence that microtubules play an active role in regulating basic biological processes, made possible by a code of tubulin modifications “
Significance for infertility and other diseases
In mice, the defect only led to reduced fertility, but not to total inability to conceive. “Since mice are known for their high fertility, a similar defect in humans could lead to male sterility,” suspects Gadadhar’s colleague Carsten Janke. However, the results may not only be relevant with regard to fertility. “Since the sperm flagella are only one of many types of cilia in our body, we think that a similar tubulin-coded regulation is important in various cilia-related functions,” the researchers say.
A similar structure with microtubules in cell processes can be found, for example, in the cilia of the lungs. Among other things, these are responsible for moving mucus and thus cleaning the bronchi. This function was apparently not impaired in the mice in the experiment, which suggests that modifications other than glycylation are important here. The same applied to cell processes in other tissues and organs such as the brain. The basic principle of microtubule modification could also open up new insights here. “Therefore, our work enables a deeper understanding of various diseases, such as developmental disorders, cancer, kidney diseases or breathing and vision disorders,” the researchers say.
Source: Sudarshan Gadadhar (Institut Curie, France) et al., Science, doi: 10.1126 / science.abd4914