Deficient forward transduction and enhanced reverse transduction in the alpha tectorin C1509G human hearing loss mutation

Abstract

SUMMARYMost forms of hearing loss are associated with loss of cochlear outer hair cells (OHCs). OHCs require the tectorial membrane (TM) for stereociliary bundle stimulation (forward transduction) and active feedback (reverse transduction). Alpha tectorin is a protein constituent of the TM and the C1509G mutation in alpha tectorin in humans results in autosomal dominant hearing loss. We engineered and validated this mutation in mice and found that the TM was shortened in heterozygous Tecta C1509G/+ mice, reaching only the first row of OHCs. Thus, deficient forward transduction renders OHCs within the second and third rows non-functional, producing partial hearing loss. Surprisingly, both Tecta C1509G/+ and Tecta C1509G/C1509G mice were found to have increased reverse transduction as assessed by sound-and electrically-evoked otoacoustic emissions. We show that an increase in prestin, a protein necessary for electromotility, in all three rows of OHCs underlies this phenomenon. This mouse model demonstrates a human hearing loss mutation in which OHC function is altered through a non-cell-autonomous variation in prestin.

Electrically evoked reticular lamina and basilar membrane vibrations in mice with alpha tectorin C1509G mutation

“…Acoustically induced reticular lamina vibration, however, is similar to the basilar membrane vibration with decreased sensitivity, broad tuning and linear growth. These findings are consistent with the discovery that the C1509G mutation resulted in deficient forward transduction and hearing loss [19]. Thus, the current micromechanics data indicate that a functional cochlear amplifier and a normal basilar membrane vibration are not required for generation and backward transmission of electrically evoked otoacoustic emission [8].…”

“…The alpha tectorin C1509G mutation mice [19] and CBA/CaJ mice at age 21 to 35 postnatal days were used in this study. Animal preparation and surgical approaches were similar to those in gerbils [5,12,13].…”

“…Mutations in tectorin caused nonsyndromic hereditary hearing loss [16]. Mice with the C1509G mutation in alpha tectorin showed deficient forward transduction and hearing loss, but enhanced electrically evoked otoacoustic emissions [3,19]. To study micromechanical mechanism of how the mutated cochlea, with a short and detached tectorial membrane and freestanding hair bundles, transmits outer hair cell-generated acoustic energy to the ear canal, we measured the electrically evoked reticular lamina and basilar membrane vibrations and otoacoustic emissions in C1509G mutation mice.…”

Three-Dimensional Imaging of the Mouse Organ of Corti Cytoarchitecture for Mechanical Modeling

“…(1) For the fixed whole-mount preparations, cochleae were fixed with 4% paraformaldehyde for 2 hours, decalcified, and dissected into 6 pieces for staining with the membrane dye Cellmask at 1:5000 for 5 minutes. (2) For the in situ fixed preparations, prestin immunolabeling was performed within the intact cochlea to visualize OHCs [9]. We also performed simultaneous phalloidin labeling to label actin [5].…”

The role of tectorial membrane stiffness and viscosity on traveling waves and resonance

“…Mouse models with specific mutations of TM components have supported this hypothesis by showing that alterations in the TM give rise to significant hearing loss [8,9,[11][12][13]. However, these studies have not elucidated the mechanistic role of the TM.…”