St. Jude Children's
Research Hospital investigators have found that an electrically powered
amplification mechanism in the cochlea of the ear is critical to the acute
hearing of humans and other mammals. The findings will enable better
understanding of how hearing loss can result from malfunction of this
amplification machinery due to genetic mutation or overdose of drugs such
as aspirin.
Sound entering the cochlea is detected by the vibration of tiny,
hair-like cilia that extend from cochlear hair cells. While the cochlea's
"inner hair cells" are only passive detectors, the so-called "outer hair
cells" amplify the sound signal as it transforms into an electrical signal
that travels to the brain's auditory center. Without such amplification,
hearing would be far less sensitive, since sound waves entering the cochlea
are severely diminished as they pass through the inner ear fluid.
In their studies, Zuo and his colleagues have sought to establish the
mechanism by which outer hair cells produce such amplification.
Specifically, they wanted to distinguish between two amplification theories
-- called "stereociliary motility" and "somatic motility" -- that have
resulted from previous studies of the auditory machinery.
The stereociliary theory holds that amplification is produced by
intricate vibrations of the bundles of cilia extending from the outer hair
cells. The somatic motility theory proposes that the sound signal is
amplified by an amplifier protein, called prestin, embedded in the hair
cell membrane. Prestin is powered by voltages within the membrane that are
produced by mechanical sound vibrations.
"This motility is also called 'dancing' because when you electrically
stimulate an outer hair cell with a sound, the cell body spontaneously
elongates and contracts along with the sound," said Jian Zuo, Ph.D.,
associate member of the St. Jude Department of Development Neurobiology.
"It is very dramatic to see these hair cells 'dance' with the sound." Zuo
is the senior author of a report on this work that appears in the May 8
issue of the journal "Neuron."
Since the prestin protein is the key component of somatic motility, in
previous experiments Zuo and his colleagues genetically knocked out prestin
in mice and tested the effects on hearing. Those mice showed a hearing
defect that indicated a malfunction of somatic motility. While the knockout
experiments were strong evidence for the role of somatic motility, the
affected mice also showed structural abnormalities in their outer hair
cells, Zuo said, thus complicating the interpretation.
In the new experiments to more unequivocally establish the role of
somatic motility, the researchers genetically altered mice to have only
subtle alterations in the prestin protein. These alterations only
compromised prestin's function as an amplifier but did not otherwise affect
the outer hair cell structure or function, the researchers' analysis
showed.
"We found that these mice showed exactly the same kinds of hearing
deficiency as the previous knockout mice," Zuo said. "Therefore, we believe
that these experiments eliminate criticism of our earlier experiments with
the knockout mice." The new experiments, Zuo said, thus firmly establish
that the "dancing" somatic motility of the outer hair cells is critical to
cochlear amplification.
However, he noted, "With this study we still cannot really exclude
stereociliary motility from contributing to cochlear amplification, because
eliminating somatic motility also reduces ciliary motility. So, it is not
possible to totally isolate either form of motility. In fact, we
hypothesize that the two mechanisms might work together in different
aspects of amplification."
By finding prestin's role in hearing Zuo and his colleagues may help
scientists better understand the mechanisms of hearing loss. "For example,
an overdose of aspirin causes a high-frequency hearing loss by inhibiting
prestin's function," Zuo said. "Also, there is evidence that many cases of
high-frequency hearing loss are caused by defects in the cell's molecular
machinery that involves prestin. And two mutations that have been detected
in the prestin gene in humans are reported to be associated with deafness."
Other authors of the paper include Xudong Wu , Jiangang Gao and Wendy
Cheng (St. Jude); Peter Dallos, Mary Ann Cheatham, Jing Zheng, Charles
Anderson and Soma Sengupta (Northwestern University, Evanston, Ill.); and
Shuping Jia, Xiang Wang and David He (Creighton University, Omaha, Neb.).
This work was supported in part by The Hugh Knowles Center at
Northwestern, the National Institutes of Health and ALSAC. Zuo is a
recipient of a Hartwell Individual Biomedical Research Award.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for
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other catastrophic diseases. Founded by late entertainer Danny Thomas and
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