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Sometime after birth, the kinocilium is lost from the hair cell in the mammalian cochlea. Although the precise role of the kinocilium remains unclear, it is believed essential to proper development of the stereocilia. Adding to the mystery is the fact that the kinocilium persists in other parts of the ear and in lower vertebrates.
"We know it's not necessary for [signal] transduction, but we can't say why it survives elsewhere in the body," says HHMI investigator A. James Hudspeth, a researcher at the Rockefeller University who has been studying signal transduction in hair cells for decades. "The only hint we have is that when the hair bundle is formed, the kinocilium develops first, and it always moves to one edge of the cell. It seems to set up the axis along which the stereocilia are subsequently polarized. But the evidence for that is still circumstantial."
Signal transduction in hair cells involves movement of the stereocilia in the direction of the kinocilium—or rather, where the kinocilium was. The mechanical action of the cilia bending somehow triggers a signal necessary to hearing. The long-held suspicion is that spring-like "tip links" extending between adjacent stereocilia physically tug open ion channels when hair bundles are deflected by sound or movement. Hudspeth and several other HHMI investigators are determined to figure out how that happens.
David P. Corey, an HHMI investigator at Harvard Medical School, has identified a protein at the tips of stereocilia—called TRPA1—that is a candidate for the mechanically sensitive channel in hair cells. "Currently, we're carrying out a number of tests, including making a knockout mouse, to see whether it's doing what we think it's doing," he reports.
Corey says TRPA1 is very similar in structure to the nompC (no mechanoreceptor potential, type C) protein discovered in the laboratory of HHMI investigator Charles S. Zuker at the University of California, San Diego. In 2000, Zuker identified the protein, which is also a member of the TRP family of ion channels and is now called TRPN1, in the sensory bristle of the fruit fly Drosophila. Interestingly, the bristle's composition is that of a true cilium: tubulin-based rather than actin-based. Corey has found TRPA1 in mouse hair cell kinocilia as well, perhaps suggesting further evolutionary conservation across species.
Teresa Nicolson, an HHMI investigator at Oregon Health & Science University, studies mutant zebrafish that swim in circles—a classic sign of inner-ear dysfunction. When she learned of Zuker's finding in the fly bristle, she thought it might be the same transduction channel as the one in hair cells. She was excited to find a version of the TRPN1 channel expressed in zebrafish hair cells.
When her lab knocked out the gene in zebrafish, they saw deafness and balance defects in the mutants. In addition, electrical potential in the channels disappeared. "The results suggest that the TRPN1 channel could be the transduction channel in zebrafish hair cells," says Nicolson. "Now we are trying to show it is actually in the right place to be doing that job."
Nicolson's lab also has a bead on the tip link protein. Her candidate, cadherin 23, has a very long extracellular domain that could serve to physically link the stereocilia tips. Labeling experiments have localized cadherin 23 to the tips of the bundles, and mutants lacking the protein have no tip links. They are also deaf.
Image: Courtesy of Bechara Kachar / NIH; Colorized SEM
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