NIDCD Team Studies Stereocilia Unique Protein Appears to Control Stereocilia Height, Formation Features
Features  |   May 01, 2011
NIDCD Team Studies Stereocilia
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Regulatory, Legislative & Advocacy / Features
Features   |   May 01, 2011
NIDCD Team Studies Stereocilia
The ASHA Leader, May 2011, Vol. 16, 5-6. doi:10.1044/leader.FTR4.16052011.5
The ASHA Leader, May 2011, Vol. 16, 5-6. doi:10.1044/leader.FTR4.16052011.5
Stereocilia are a wonder of micro-engineering—they perch like a bristly, V-shaped battlement atop sensory cells that line the inner ear. Grouped in precisely ordered rows rising like a staircase from front to back, these bundles of super-sensitive fibers are the structures (or organelles) responsible for converting vibrations that enter the ear into electrical signals that travel to the brain and say “sound.”
Scientists know quite a bit about stereocilia—they know, for example, that bundled filaments of a protein called actin make up each stereocilium. Actin filament bundles appear in many other types of cellular structures, such as the microvilli that line the small intestine and help in the absorption of nutrients from food. Scientists also know that stereocilia are linked by a system of horizontal filaments that connect the shorter ones to their taller neighbors so that the whole bundle moves as one unit when it’s stimulated by sound. What isn’t known, however, is how stereocilia know when to stop growing. Because their precise height and staircase formation are essential to hearing, there must be strong regulatory functions within the cell to control their length.
Researchers at the National Institute for Deafness and Other Communication Disorders (NIDCD) at the National Institutes of Health have identified a new protein that appears to work together with two already known proteins to regulate stereocilia length. This important discovery by NIDCD scientist Bechara Kachar, his Laboratory of Cell Structure and Dynamics, and a cadre of international researchers builds on efforts for several decades to understand the complex structure and assembly of sterocilia. The findings have been published in the Jan. 25, 2011, issue of Current Biology.
“Stereocilia lengths are regulated with incredible precision,” said researcher Uri Manor, “with no more than a few nanometers of difference among those in the same row.”
The scientists’ search for a mechanism that could make and maintain stereocilia at such an extraordinary level of precision was built on previous studies conducted in mice hair cells. These studies examined proteins that are unique to stereocilia, including the motor protein myosin XVa and another protein called whirlin. Gene mutations associated with the two proteins are known to cause several different forms of hearing loss and vestibular dysfunction.
Previous experiments have established that stereocilia lacking either myosin XVa or whirlin are abnormally short, indicating that the two proteins must somehow be involved in stereocilia growth. Also, researchers have shown that the two proteins cluster in abundant numbers at the tips of normal stereocilia. However, as neither protein appears to have the ability to regulate actin bundle lengths, they were unlikely to be responsible for determining stereocilia length.
Kachar and his colleagues turned to another protein—Eps8—that was known from earlier studies to regulate actin bundle growth in other kinds of cells. “No one had thought about looking at this protein in hair cells,” Kachar said, “but a group in Italy that had been involved in characterizing its function contacted us about Eps8, so we thought it was worth a try to see if we could find Eps8 in stereocilia.”
In collaboration with researchers at the FIRC Institute of Molecular Oncology Foundation and the Universita degli Studi di Milano in Milan, Italy, the team was able to show that Eps8 localized at the tips of stereocilia. Even more interesting, Eps8 was present in amounts that were proportional to the length of each stereocilium—there was more of it in long ones and less of it in short ones. Further experimentation established that hair cells from mice that lacked Eps8 have very short stereocilia, clarifying that Eps8 was regulating the lengths of stereocilia.
A series of experiments using immunofluroescence markers to make the proteins visible showed striking similarities in the localization of Eps8, myosin XVa, and whirlin in stereocilia tips, as well as the shortening of stereocilia when the proteins were absent. Notable was that without myosin XVa, Eps8 could not be found in the stereocilia tips. However, if whirlin was absent, Eps8 could be found, but only in smaller amounts. These findings gave the researchers enough information to hypothesize how the three proteins might interact to regulate actin bundle elongation and therefore the length of stereocilia.
According to Kachar, myosin XVa, Eps8, and whirlin are part of a system of regulated protein assembly. “Myosin XVa is the motor element that transports Eps8 and whirlin to the tips,” he said. “Eps8 is the actin-regulating element that determines stereocilia length, and whirlin has scaffolding properties that help accumulate this complex at the tips.”
The researchers have already shown that mice without Eps8 are deaf. It is likely that the absence of Eps8 in humans also could cause loss of hearing. Next they’ll be looking at the molecular details involved in exactly how Eps8 regulates stereocilia length. Manor says that Eps8 has several regulatory domains—areas of the protein that contain actin-controlling activities. “One domain caps filaments,” he explained, “which would normally be expected to shorten actin filaments. Another domain crosslinks filaments, which could be one way of stabilizing and elongating actin bundles. It will be interesting to see how the cell uses a specific molecule with seemingly contradictory activities to regulate so dramatically the length of an actin protrusion.”
(This article was adapted from a news release retrieved on March 15, 2011, from the website of the National Institute for Deafness and Other Communication Disorders.)
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May 2011
Volume 16, Issue 5