It turns out that not all the hairlike cilia projecting from the surfaces of many cells in the human body are equal—there are the myriad ones for sweeping, swimming and other functions, and then there is the until recently mysterious primary cilium.
Nearly all human cells contain these numerous microscopic projections. The more abundant variety of cilia are motile; they act like oars, paddling in coordinated waves to help propel cells through fluid, or to sweep material across cellular surfaces (as in the respiratory system, where millions of cilia lining the airways help to expel mucus, dead cells and other bodily debris). By contrast, cells also contain a single, nonmotile cilium known as the primary cilium. Its presence on cells has been known for more than a century, but many believed it was a functionless evolutionary remnant.
Within the last decade, evidence has emerged demonstrating that the primary cilium does indeed have a function. For instance, the primary cilium is required for the ability of retinal cells to detect light, for cells of the olfactory system to detect odors, and is critically involved in an array of other cell communication processes.
What all these diverse cell activities have in common are specific cell surface receptors that receive sensory signals and relay the information into the cell. Much of this cell communication machinery occurs at the primary cilium, partly because this organelle extends out from the cell body where it can access environmental signals. Thus, the primary cilium serves as a sort of molecular antenna, receiving and transmitting signals for the cell.
Just how a cell's specific receptors migrate from the cell's plasma surface membrane to the cilium has remained incompletely understood. Recent research led by Maxence Nachury, professor of molecular and cellular physiology at Stanford University, published June 25 in the journal Cell, has added some new molecular details.
Nachury and his colleagues focused on understanding the BBS family of proteins, so named because defects in these proteins cause dysfunction of primary cilia and the rare genetic disease known as Bardet–Biedl syndrome (BBS). BBS patients experience retinal degeneration, along with a loss of their sense of smell; many sufferers also tend to have other symptoms, including extra fingers and toes, diabetes, obesity and kidney disease, suggesting that primary cilia play broad roles in human health.
"All of these symptoms are present in BBS patients from a very early age," Nachury says. For instance, by six to 12 months of age, individuals are already massively obese; around age five their retinas degenerate, and by adolescence they are legally blind.
Remarkably, a wide range of organ dysfunction can result from abnormalities in this very inconspicuous organelle, the primary cilium. "That was really a wake-up call for a lot of cell biologists. This is something important here," Nachury says.
There are 14 known BBS genes, any of which, when mutated, can give rise to the disease. Protein products from seven of these genes assemble into a complex, known as the BBSome, previously discovered by Nachury's lab. The precise function of BBS, however, proteins remained unclear. "At the time, we were quite pleased to have a unifying hypothesis for BBS, where a biochemical entity brought a lot of these gene products together. But as far as function, it was still something that was eluding us," Nachury says.
Prior research by Michel Leroux, professor of molecular biology and biochemistry at Simon Fraser University in British Columbia who did not participate in the study, demonstrated that BBS proteins help move other proteins within the cilium, likely helping to target proteins to or from this cellular compartment. The new study provides evidence that BBS proteins also assist in the delivery of receptor proteins to the surface of the cilium. Using mouse neuronal cells, the researchers discovered that the BBSome sorts a receptor present on the plasma membrane (cell surface) and targets the receptor to the cilium where it functions. "The BBSome grabs onto a specific membrane protein and drags it into the ciliary membrane," Nachury says.
"All these different symptoms we're seeing [in BBS patients] could very likely be caused by specific receptors that did not make it to the cilium, and therefore specific signaling pathways didn't get to signal properly," Nachury says.
Next, the researchers are interested in identifying other receptors that might be transported by the BBSome. One possibility involves the way in which the brain senses the amount of fat in the body, a process that is believed to depend on a receptor known to interact with a BBS protein. Therefore, future studies may address how cilium-based cell communication regulates body weight and obesity.
This research could also be helpful in the development of drug therapies that help balance problems associated with the function of cilia. "In people that may have obesity problems, for example, one could imagine a way to specifically modulate either the functions of the BBS proteins or other proteins that help the trafficking of key receptors to cilia or to alter the ciliary signaling pathways, such as to improve the clinical symptoms," Leroux says.