Overlooked Cell Structure Plays Key Role in Brain Development

A microscopic, antenna-like structure found in nearly every cell in the human body may have a far greater influence on brain development than previously recognized. New research from the University of California, Riverside published in Cell Reports sheds light on the primary cilium—an organelle that has remained surprisingly understudied despite its presence in almost every human cell—and its potential connection to developmental disorders.

"Even many biologists aren't familiar with it," said Xuecai Ge, lead researcher on the study. "We still have a lot to learn about this organelle."

For decades, scientists considered the primary cilium an evolutionary leftover with little function. Mounting evidence has since pointed in a different direction. When the structure is disrupted, it can lead to a group of conditions known as ciliopathies, which affect multiple organs including the brain. Patients with ciliopathies may experience kidney problems or obesity, but brain abnormalities are also common— n observation that prompted Ge's team to investigate what role the cilium might play in brain development.

The researchers focused on neural progenitor cells, early-stage cells that give rise to neurons. Each contains a single primary cilium that extends into the ventricles, the fluid-filled cavities of the developing brain. Using a large-scale biochemical approach, the team analyzed more than 1,000 mouse embryonic brains to identify which proteins are present in these cilia.

"We discovered many proteins that no one expected to find in the cilium," Ge said. "And in some cases, these proteins are directly linked to human developmental disorders."

 One such protein, CKAP2L, is associated with Filippi syndrome, a condition that leads to reduced brain size. When the researchers removed this protein in mice, the animals developed smaller brains. The team also identified more than 40 proteins that vary between brain regions, suggesting the cilium serves specialized roles rather than a single uniform function across the brain.

Perhaps the most unexpected finding was evidence that protein production may occur directly inside the cilium itself—a concept that runs counter to longstanding scientific thinking. "The field has assumed that all proteins are made elsewhere in the cell and then transported into the cilium," Ge said. "But we found the machinery that could make proteins on-site. It's like finding a bread maker where you thought bread could only be delivered."

Further research is needed to confirm whether this machinery is active. But if validated, the finding could represent a significant shift in how scientists understand cellular function.

The research also has implications for understanding and potentially treating ciliopathies, which can affect vision, organ function, and brain development. "Understanding which proteins are in the cilium and what they do gives us a roadmap," Ge said. "It helps us connect genetic mutations to the actual biological processes that go wrong."

Ge's team plans to continue investigating which proteins are produced within the cilium. "We've only scratched the surface," she said. "There's a lot more to learn about how this tiny structure shapes the developing brain."