Breaking the code of sperm motion: Two proteins found to be vital for male fertility

Osaka, Japan – There are many potential causes of infertility, and it can be challenging to pin down just what the problem is when a couple is having trouble getting pregnant. Now, researchers show that a few key proteins have a major effect on sperm development, and therefore male fertility.

In a study published this month in Nature Communications, researchers from The University of Osaka have revealed that proteins forming a specialized structure are required for correct sperm function.

Sperm are propelled by flagella, which are like long whips whose motion propel sperm forward. Sperm whose flagella don’t work very well do not travel quickly or efficiently, so they are less likely to result in a successful pregnancy. Thus, anything that affects the function of flagella is likely to cause male infertility.

“The structure of the sperm flagellum is quite complex and includes radial spokes, which are essential for controlling flagellar motion,” says lead author of the study Haoting Wang. “CFAP91 is a radial spike protein and has been implicated in human male infertility, but it is unclear why it has this effect.”

To explore the role of CFAP91 in sperm development and function, the researchers generated mice that did not express this protein and evaluated the shape and movement of their sperm. The researchers re-expressed CFAP91 in the same mice to figure out what other proteins it interacts with. They then used a technique called proximity labeling to identify even more related proteins in fully developed sperm.

“The results were very clear,” explains Haruhiko Miyata, senior author. “Cfap91 knockout mice not only exhibited impaired sperm flagellum formation, but also had male infertility.”

When CFAP91 was re-expressed in the mice, the researchers found that it interacted with known radial spoke proteins. In addition, proximity labeling analysis showed that EFCAB5 is a CFAP91-proximal protein that helps regulate sperm movement.

“Our findings show that CFAP91 affects male fertility because it serves as a scaffold for assembling the radial spokes. In addition, we showed that the nearby protein EFCAB5 is crucial for controlling specialized sperm movement,” says Haoting.

The findings from this study highlight the complexity of sperm structure in humans and how it contributes to male fertility. Understanding how these proteins function helps understand male infertility and could help develop new targets to diagnosis infertility.

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The article, “Proximity Labeling of Axonemal Protein CFAP91 Identifies EFCAB5 that Regulates Sperm Motility,” will be published in Nature Communications at DOI: https://doi.org/10.1038/s41467-025-63705-7.

About The University of Osaka

The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en