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Some cilia are rigid spikes that act as antennae, gathering sensory information for the cell from the surrounding environment. Other cilia are flexible and whip-like, capable of registering the surrounding fluid's flow and ebb.
Scientists have recently implicated malfunctioning cilia as factors in a number of diseases. One of the most devastating among them is the heritable Bardet-Biedl syndrome (BBS)—a rare disorder, involving multiple organ defects, that results in obesity, retinopathy, polydactyly (more than five digits on the hands or feet), kidney disease, and mental retardation, among other problems. HHMI investigator Val C. Sheffield at the University of Iowa Carver College of Medicine is among the scientists trying to get at the genetic origins of the disorder. So far, at least eight genes have been tied to BBS, several of which Sheffield's lab identified, and all of them have been linked to ciliary function.
But it was another malady affecting the kidney—polycystic kidney disease, or PKD—that fed the current surge of interest in cilia and what they do. It began when a group of scientists saw something in common between a mouse and a single-celled plant.
Primary cilia were first described in 1898. For the next hundred years or so cell biologists largely ignored them, but microscopists continued to document their presence in the cells of most vertebrate organisms. It was generally believed that the nonmotile cilium was either a sensory organelle, because of its presence in the nose and eye, or that it no longer served any purpose. Understanding the role of the motile cilium and the flagellum (a structure nearly identical to the cilium) was easier. They provide movement, as in sperm and in the lungs and trachea of the respiratory tract.
In the 1990s, researchers began to understand more about the internal workings of cilia and flagella, and how cargo moves up and down the microtubular tracks within them. During such intraflagellar transport (IFT), large protein complexes are carried to the ciliary tip and then back to the cell body. "You can think of the IFT particle as the equivalent of railroad cars," says Gregory J. Pazour, a researcher at the University of Massachusetts Medical School. "It carries materials needed to build the cilia and returns with spent materials." Pazour suspects that the IFT particle, which is made up of at least 17 polypeptide subunits, may also carry signals—messages collected by various receptors embedded in the ciliary membrane—back from the tip.
During the late 1990s, Pazour partnered with Joel Rosenbaum at Yale University, Douglas Cole at the University of Idaho, and George Witman at the University of Massachusetts Medical School to purify and sequence subunits of the IFT particle isolated from the unicellular alga Chlamydomonas. In October 2000, the Journal of Cell Biology published their finding that one of the alga particle's subunits—termed IFT88, or polaris—is encoded by a gene that is homologous to the mouse and human gene Tg737. They observed that mutant Chlamydomonas lacking the IFT88 gene are normal—except for the absence of flagella. And, it turns out, mice with defects in Tg737 die shortly after birth from PKD.
The evidence suggested that IFT is important for primary cilia assembly and that defects in ciliagenesis in the kidney can lead to PKD. So the researchers got the defective mice, publicly available from the Oak Ridge National Laboratory, and looked at their kidneys.
"As we predicted," says Pazour, "the kidney cilia were aberrantly formed. This evidence laid to rest the idea that kidney cilia had no function—that they were vestigial organelles. That was pretty exciting for us."