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Sensory Transduction by Hair Cells of the Inner Ear
Summary: Jim Hudspeth studies the biophysical and molecular bases of hearing and equilibrium; in particular, he is interested in the development and operation of the inner ear's sensory receptors, the hair cells.
Thirty million Americans have significant hearing problems that range in severity from modest difficulty with speech comprehension to profound deafness. Hearing impairment affects people of all ages. One child in a thousand is born deaf, and another one in a thousand becomes deaf before adulthood. A quarter of our population over 60 years of age is hearing-impaired, and half of those older than 80 are afflicted.
Most deaf individuals suffer from sensorineural hearing loss that results from damage to hair cells, the sensory receptors of the inner ear. Each cochlea normally contains about 16,000 hair cells, which convert mechanical inputs derived from sound into electrical signals that the brain can interpret. Similar cells in the vestibular labyrinth mediate responsiveness to acceleration and thus underpin our sense of balance. Human hair cells may be lost throughout life as a result of genetic conditions, infections, ototoxic drugs, acoustical trauma, and aging. Because these cells are not replaced by cellular division, their disappearance is associated with a gradual decline of our senses of hearing and equilibrium. In the hope of understanding normal hearing—as well as its development, its deterioration, and its possible restoration—our group is investigating the molecular structure and operation of hair cells from the vertebrate internal ear.
Coherent Motion of Stereocilia in the Hair Bundle
The hair cell's mechanoreceptive organelle, the hair bundle, is highly sensitive because its transduction channels open over a very narrow range of displacements. The synchronous gating of transduction channels also underlies the active hair-bundle motility that amplifies and tunes responsiveness. The extent to which the gating of independent transduction channels is coordinated depends on how tightly individual stereocilia are constrained to move as a unit. We therefore wished to understand how signals propagate across a hair bundle to affect the full complement of channels.
A conclusive examination of the propagation of mechanical forces across a bundle requires simultaneous measurements of the positions of two stereocilia with a subnanometer spatial and a submillisecond temporal resolution, for these are the scales typical of stereociliary movements during hearing. Because interferometry can detect motions with the requisite precision, we constructed a dual-beam, differential laser interferometer and used it to examine the correlations between the thermal motions of individual stereocilia, in both quiescent and spontaneously oscillating hair bundles. We found that thermal movements of stereocilia located as far apart as the bundle's opposite edges display high coherence and zero phase lag over a wide range of frequencies. In other words, the distinct stereocilia move synchronously and to the same extent. Because the mechanical degrees of freedom of stereocilia are strongly constrained, a force applied anywhere in the hair bundle deflects the structure as a unit. This assures the concerted gating of transduction channels that maximizes the sensitivity of mechanoelectrical transduction and enhances the hair bundle's capacity to amplify its inputs. (These experiments have been supported in part by a grant from the National Institutes of Health.)
The Origin and Polarization of Regenerating Hair Cells in the Zebrafish's Lateral Line
An epithelial cell is polarized along its apicobasal axis and often also perpendicular to this axis, within the plane of the epithelium. The latter type of cellular organization, termed planar cell polarity, is exemplified by the orientation of the hair bundle that projects from the apical surface of each sensory hair cell. Because the hair bundle's axis of morphological polarization defines the cell's axis of responsiveness to mechanical stimuli, the senses of hearing and equilibrium rely on the coordinated orientation of hair cells across the sensory epithelium.
The restoration of planar cell polarity is an essential but poorly understood step toward physiological recovery during sensory-organ regeneration. We investigated this issue in the lateral line of the zebrafish by observing the production of new hair cells after lesioning with an aminoglycoside antibiotic. We identified a molecular marker that permitted us to recognize for the first time a population of transient hair-cell progenitors that are produced by putative stem cells. Within each neuromast, hair cells regenerate in pairs along a single axis established by the restricted localization and oriented division of their progenitors. By analyzing mutants lacking the planar-polarity determinant Vangl2, we ascertained that the uniaxial production of hair cells and the subsequent orientation of their hair bundles are controlled by distinct pathways, whose combination underlies the establishment of hair-cell orientation during development and regeneration. This mechanism may represent a general principle governing the long-term maintenance of planar cell polarity in remodeling epithelia. (These experiments have been supported in part by a grant from the National Institutes of Health.)
Analysis and Functional Evaluation of the Hair-Cell Transcriptome
An understanding of the molecular bases of the morphogenesis, organization, and functioning of hair cells requires that the genes expressed in these cells be identified and their functions ascertained. After purifying zebrafish hair cells and detecting mRNAs with oligonucleotide microarrays, we developed a subtractive strategy that identified 1,037 hair cell-expressed genes whose cognate proteins subserve functions including membrane transport, synaptic transmission, transcriptional control, cellular adhesion and signal transduction, and cytoskeletal organization. To assess the validity of the subtracted hair-cell data set, we verified the presence of 11 transcripts in inner-ear tissue. Functional evaluation of two genes from the subtracted data set revealed their importance in hair bundles: zebrafish larvae bearing the seahorse and ift172 mutations display specific kinociliary defects.
The data set resulting from our study should help researchers identify genes relevant to hair-cell development and operation. For example, in a preliminary search for candidate genes that underlie heritable deafness, we have identified a human ortholog of a zebrafish hair-cell gene whose map location is bracketed by the markers of a deafness locus. (These experiments have been supported in part by a grant from the National Institutes of Health.)
Last updated: August 29, 2007
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