December 9, 2005
SAN FRANCISCO - For many years scientists believed that cilia - small hair-like projections on the surface of cells - were merely nonfunctioning remnants of past evolution. But new findings by researchers at the University of Alabama at Birmingham (UAB) challenge this thought, demonstrating cilia play an essential role in the proper formation of certain tissues, such as limbs and digits, and in the development of some diseases and disorders, such as basal cell carcinoma and hydrocephalus. Details of recent studies are being presented at the annual Cell Biology Conference, Dec. 10-14, in San Francisco.
"Our findings suggest cilia are directly involved in the processing and activation of certain proteins, called Gli proteins," said Bradley Yoder, Ph.D., associate professor of cell biology at UAB. "Normal regulation of these proteins is essential for proper development of many tissues, including formation of digits of limbs. The loss of cilia and subsequent processing or activation of these proteins results in severe defects in how the limb forms."
Studies focused on a protein called Tg737/polaris, required for cilia formation. "In mice, we found if the function of this protein is disrupted, it results in short limbs with an excess number of digits," said Yoder.
Researchers discovered that Tg737 and primary cilia are needed for a cell to sense and respond to a signaling molecule known as sonic hedgehog, previously shown to regulate Gli proteins. "Our study shows that in the absence of Tg737, the processing of Gli proteins is altered, which disrupts the signaling pathway, resulting in limb abnormalities."
New insight gleaned from this work may have application for better understanding the development of certain diseases, such as basal cell carcinoma, one of the most common
forms of skin cancer. "Sonic hedgehog signaling is a very complex, powerful pathway essential for the development of most mammalian tissues," Yoder said. "Over activation of this signaling pathway is directly linked to basal cell carcinoma. Therefore, our finding may provide important insights into the development of this disease."
In another study, researchers examined the role of cilia in hydrocephalus, an abnormality characterized by the buildup of cerebrospinal fluid (CSF) in the ventricles of the brain. "In this study, as well, findings show that cilia dysfunction plays a critical role in development of this condition," Yoder said.
In the U.S., one in 1,000 babies is born with hydrocephalus, one of the most common birth defects. Over the last 25 years, the death rate from hydrocephalus has declined dramatically. However, there remains no cure, and while there are effective treatments, many children born with hydrocephalus also will have some form of intellectual and/or motor disability.
Researchers found cilia are responsible for the movement of CSF through the brain's ventricles. "In mice with partial loss of Tg737, cilia form but appear very disorganized and stunted," Yoder said. "Consequently, the beating of these abnormal cilia is unable to move fluid through the ventricles at a normal, rapid pace."
Also, with hydrocephalus, findings suggest cilia play a role in increased production of CSF. "This is the first study to examine the role of cilia found in the choroid plexus (CP), the structure within the brain that produces CSF," Yoder said. "From our study, we believe loss of cilia results in an increase in sodium and chloride transport in the CP, which leads to increased CSF production."
The research was funded, in part, by grants from the March of Dimes Foundation, a non-profit organization dedicated to improving the health of babies by preventing birth defects, premature birth and infant mortality.