CCDC180 functions as a C1 projection scaffold essential for ciliary motility and male fertility

Inside the microscopic world of our bodies, tiny hair-like structures called cilia and flagella act as the engines of movement. Found on the surface of many cells, these appendages beat in rhythmic, coordinated waves to push fluids along. In the brain, they circulate cerebrospinal fluid, acting like a river current that clears waste and nourishes tissue. In the reproductive system, they are the propellers that drive sperm forward. For these structures to work, they rely on a precise internal skeleton. At the very center of this skeleton lies a complex machine known as the central apparatus, a pair of microtubules decorated with protein projections that act as a control panel, ensuring the beating motion stays straight and efficient. When this machinery fails, the consequences can be severe, leading to chronic respiratory infections, infertility, or a dangerous buildup of fluid in the brain.

A team of researchers at Shandong Normal University has now identified a critical piece of this machinery, a protein called CCDC180, and shown exactly what happens when it is missing. By creating mice that lack this specific protein, the scientists discovered that CCDC180 serves as an essential scaffold, a structural framework that holds other vital components in place within the central apparatus. Without it, the internal control system of the cilia collapses. In male mice, this failure causes sperm to lose their ability to swim and even their shape, leading to complete infertility. In the brain, the cilia stop beating in a coordinated line and instead spin uselessly, causing fluid to accumulate and resulting in hydrocephalus. This work reveals that CCDC180 is not just a passive part of the structure but a linchpin required for the entire assembly to function, offering a new explanation for certain cases of human infertility and brain disorders.

To understand the role of this protein, the researchers first looked at where it lives in the body. They found that the gene for CCDC180 is highly active in tissues packed with moving cilia, such as the testis, the lung, and the brain. Evolutionary analysis showed that this protein has been preserved across millions of years, appearing in everything from single-celled algae to humans, suggesting it performs a fundamental job that cannot be easily replaced. Using advanced microscopy, the team visualized the protein inside the cilia of cultured brain cells. They saw that CCDC180 sits along the central core of the cilium, appearing as distinct dots that line the length of the structure. When they tried to break the protein into smaller pieces to see which part was responsible for getting it into the cilium, they found that the full, unbroken protein was necessary for proper placement, indicating it acts as a long, continuous structural beam.

The scientists then turned to the living animal to see what happens when this protein is gone. They used gene-editing tools to create mice that completely lacked CCDC180. These mice were born healthy and looked normal at first glance, surviving infancy without immediate issues. However, as they grew, two distinct problems emerged. First, the male mice became completely sterile. When paired with normal females, they produced no offspring, whereas the females of the same strain remained fertile. Second, the mice developed hydrocephalus, a condition where fluid builds up in the brain. Brain scans showed that the fluid-filled spaces in the brain had expanded, a clear sign that the fluid was not flowing properly. Interestingly, the respiratory system seemed less affected; the mice did not show the severe mucus buildup often seen in other cilia-related diseases, suggesting that different tissues rely on this protein to varying degrees.

Digging deeper into the cause of male infertility, the researchers examined the sperm. In a normal mouse, the epididymis, a tube where sperm mature, is packed with healthy, swimming cells. In the mice without CCDC180, this tube was nearly empty. The few sperm that were present were malformed. Instead of the long, whip-like tails needed for propulsion, many had tails that were short, coiled, or missing entirely. Some sperm also had misshapen heads. The team used high-speed cameras to watch the few remaining sperm try to move. Instead of swimming forward, they struggled to generate any forward motion. This confirmed that the lack of CCDC180 destroyed the structural integrity of the sperm tail, preventing the animal from reproducing.

The story was different, but equally revealing, in the brain. The researchers looked at the cilia lining the brain's ventricles, which are responsible for moving the cerebrospinal fluid. Under a microscope, the cilia were still present and attached to the cells, meaning the protein was not needed to build the cilia in the first place. However, their movement was wrong. In a healthy mouse, the cilia beat in a coordinated, flat plane, pushing fluid in one direction like oars on a boat. In the mice without CCDC180, a significant portion of the cilia stopped beating in a line and instead spun in circles. This rotational movement is useless for moving fluid forward. The researchers traced this failure to the internal structure of the cilium. A normal cilium has a central pair of microtubules that act as a guide. In the mutant mice, this central pair was often disorganized or missing entirely.

The final piece of the puzzle explained why the central pair fell apart. The researchers discovered that CCDC180 acts as a docking station for other proteins. Specifically, it is required to recruit two other proteins, CFAP74 and CFAP46, to the central structure. Without CCDC180, these essential components failed to assemble, causing the entire central apparatus to become unstable. It is as if the central beam of a bridge was missing its bolts; the structure could not hold its shape, and the mechanism that directs the beating motion failed. While other parts of the central structure remained intact, the loss of these specific components was enough to disrupt the entire system.

This study provides a clear map of how a single protein supports the complex machinery of cell movement. It shows that CCDC180 is not merely a structural filler but a critical organizer that ensures the central control system of cilia is built correctly. The findings explain why the absence of this protein leads to such specific and devastating outcomes: the sperm cannot swim because their tails are structurally unsound, and the brain fills with fluid because the cilia have lost their ability to beat in a coordinated direction. By identifying this protein as a key factor in these failures, the research offers a new target for doctors to consider when diagnosing cases of unexplained male infertility or hydrocephalus, turning a microscopic structural detail into a potential clue for human health.