Unraveling a Cellular Mystery
By Matt Windsor
Once dismissed as the cellular equivalent of tonsils, primary cilia are now known to be invaluable antennae that help cells sense their environment. UAB's Bradley Yoder has helped connect primary cilia with a host of human ailments, from kidney disease to obesity and even cancer. At top, primary cilia (colored green and red) protrude from renal epithelial cells grown in culture.
In cell biology, as in love, you often don’t know what you’ve got till it’s gone. For more than a century, scientists have known that most cells in the human body come equipped with an odd projection on their outer surfaces called the primary cilium. Unlike the wavy, hairlike cilia you may remember from biology class—the ones that sweep mucus out of the airways—the primary cilia are rigid and didn’t seem to have any useful function. They were written off as vestigial, like tonsils or the appendix.
But 10 years ago, a handful of cell biologists including UAB’s Bradley Yoder, Ph.D., began to unravel the secrets of this obscure organelle. Starting in green algae and only lately moving up to humans, they made a startling discovery: If a cell loses its cilium, bad things begin to happen. Their investigations have revealed that, far from being an artifact, the primary cilium is actually an important communications device—and a major player in human growth and development, kidney disease, obesity, wound healing, and even cancer.
“Human patients with ciliary defects are often blind, they can’t smell, and they have difficulty hearing,” says Yoder. “It turns out that the cilia are loaded with receptors and channels that allow a cell to sense its environment and communicate with that environment.”
Cilia in the embryo help determine the overall body plan, including the key directive to put the heart just to the left of the centerline. (One genetic defect in the cilia causes people to be born with a completely reversed body plan, says Yoder: “Everything’s on the wrong side.”) Cilia on the rods and cones of the eye gather and respond to light. Cilia in the nose sense and react to odors. Primary cilia are involved in so many sensory functions, Yoder says, that they have earned the name “the antennae of the cell.”
Going With the Flow
Primary cilia are normally rigid, but they can bend, and this turns out to be one of the crucial functions of the cilium. Kidney cells, for example, point their cilia out into the fluid-carrying nephrons of the kidneys. “As the fluid moves, the cilia bend, and that sends a signal of how much urine you’re producing,” Yoder says. If the cilia are damaged and can’t bend, kidney cells start to run amok. The cells grow uncontrollably, to the point that they create cysts that clog the kidneys and keep them from carrying out their normal filtering function.
In fact, defective cilia lie at the heart of polycystic kidney disease, “one of the most common genetic disorders in humans and one of the leading causes of dialysis,” says Yoder. His lab narrowly missed reporting that breakthrough, but it was the first to announce another potentially blockbuster find: a link between cilia and obesity.
The cilia on some neurons in the brain contain receptors for melanin-concentrating hormone and possibly leptin—two vital parts of the body’s feeding-response system. These hormones mediate the sensation of being full or hungry to control feeding behavior; MCH induces feeding, while leptin represses the urge to eat. Mice with damaged cilia “can’t control their eating,” says Yoder. “They don’t understand when they’re full.” This fits with the clinical evidence in humans; obesity is a common symptom of many syndromes related to ciliary dysfunction.
The Call of the HedgehogYoder also helped break the news that the cilia antennae are responsible for receiving one of the most important signals in the body—the so-called Sonic hedgehog protein, which promotes cell growth. Hedgehog is crucial to normal development, but because it is so powerful, it is also tightly regulated. If the protein signals are too strong during the embryonic stage, a child may be born with excess fingers on each hand, or cyclopia (a single eye), or cleft palate, or a highly malignant form of brain tumor called medulloblastoma. If the hedgehog pathway is over activated in adulthood, it can lead to abnormal cell growth and cancer, including basal cell carcinoma. the most common form of skin cancer. Research by Yoder and others suggests that cilia not only receive hedgehog signals but that they also are deeply involved in this regulatory process.
At least one pharmaceutical company is already testing a compound that dampens hedgehog signaling to gauge its effectiveness against basal cell carcinoma, colorectal cancer, and ovarian cancer.
Cilia also play a crucial role in cell division—which is key to healthy growth but also to cancer, when cells start to reproduce uncontrollably. “For a cell to divide, the first thing it has to do is bring in the cilium,” Yoder says—the entire complex cilia apparatus is disassembled and then reassembled in the cell’s progeny.
That makes the cilium a potentially inviting target for new cancer treatments, Yoder says. “If we could find a way to make sure that the cilium can’t be reabsorbed, we should be able to stop that cell from dividing, and we would not have cancer.”
This is still only a hypothetical possibility, Yoder hastens to add. Targeting cilia as a whole isn’t promising, since they play key roles in so many different parts of the body. But “there are signals that tell a cell to bring in the cilium,” Yoder says. “If we could figure out what those are and how to block them specifically, we may have a better handle on regulating cancer and cell-division rates.”
Brain WavesDespite the recent exponential growth in cilia research, scientists keep uncovering fresh surprises. Yoder is particularly excited about the possibilities in the brain. “One of the mysteries we are tackling in my lab is the function that cilia play on neurons,” Yoder says. He has a hunch that neuronal cilia could be important in regulating mood and behavior, learning, and memory.
“There’s a single cilium sticking off the cell body of almost every central nervous system neuron,” he says. Suggestively, these cilia are packed with receptors for serotonin, somatastatin, and other key neurotransmitters involved in mood response and depression, for example. But their function remains a mystery. “What’s the cilium doing there?” wonders Yoder. “Why does a neuron need it, when it has all these other processes that specialize in communication? Is this another, underappreciated communication role that we need to understand?”
These are the kinds of endlessly intriguing questions that originally attracted Yoder to cilia in the first place, and have kept him busy ever since. “The data is clear that cilia are doing absolutely essential things,” he says. “We just need to figure out exactly what they’re doing. Then we can start to figure out how to repair or manipulate them.”