Harmonin-b, an actin-binding scaffold protein, is involved in the adaptation of mechanoelectrical transduction by sensory hair cells

We assessed the involvement of harmonin-b, a submembranous protein containing PDZ domains, in the mechanoelectrical transduction machinery of inner ear hair cells. Harmonin-b is located in the region of the upper insertion point of the tip link that joins adjacent stereocilia from different rows and that is believed to gate transducer channel(s) located in the region of the tip link's lower insertion point. In Ush1cdfcr-2J/dfcr-2J mutant mice defective for harmonin-b, step deflections of the hair bundle evoked transduction currents with altered speed and extent of adaptation. In utricular hair cells, hair bundle morphology and maximal transduction currents were similar to those observed in wild-type mice, but adaptation was faster and more complete. Cochlear outer hair cells displayed reduced maximal transduction currents, which may be the consequence of moderate structural anomalies of their hair bundles. Their adaptation was slower and displayed a variable extent. The latter was positively correlated with the magnitude of the maximal transduction current, but the cells that showed the largest currents could be either hyperadaptive or hypoadaptive. To interpret our observations, we used a theoretical description of mechanoelectrical transduction based on the gating spring theory and a motor model of adaptation. Simulations could account for the characteristics of transduction currents in wild-type and mutant hair cells, both vestibular and cochlear. They led us to conclude that harmonin-b operates as an intracellular link that limits adaptation and engages adaptation motors, a dual role consistent with the scaffolding property of the protein and its binding to both actin filaments and the tip link component cadherin-23

\u3ci\u3eGrxcr2\u3c/i\u3e is required for stereocilia morphogenesis in the cochlea

Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity

Grxcr2 is required for stereocilia morphogenesis in the cochlea

Contains fulltext : 196393.pdf (publisher's version ) (Open Access)Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity

Molecular frame photoemission in dissociative ionization of H-2 and D-2 induced by high harmonic generation femtosecond XUV pulses

International audienceWe report the first results of molecular frame photoelectron emission for dissociative photoionization (DPI) of H2 and D2 molecules induced by a spectrally filtered single high harmonic of a few femtosecond duration, using coincident electron-ion velocity vector correlation techniques. For the studied photon energies around 32 eV, where the resonant excitation of the Q1 and Q2 doubly excited states occurs, autoionization and nuclear dynamics are coupled on a few femtosecond timescale, giving rise to quantum interferences. Molecular frame photoelectron angular distributions (MFPADs), traced as a function of the kinetic energy release of the atomic fragments, provide the most sensitive observables for such complex dynamics. These results compare well with recent spectrally resolved experiments using synchrotron radiation which are also reported. As a novel XUV light source running at multi-kHz repetition rate and synchronized with laser pulses, high-order harmonic generation (HHG) opens new possibilities for extending these investigations to time-resolved studies at the femtosecond scale

Channel gating forces govern accuracy of mechano-electrical transduction in hair cells

Sensory hair cells are known for the exquisite displacement sensitivity with which they detect the sound-evoked vibrations in the inner ear. In this article, we determine a stochastically imposed fundamental lower bound on a hair cell's sensitivity to detect mechanically coded information arriving at its hair bundle. Based on measurements of transducer current and its noise in outer hair cells and the application of estimation theory, we show that a hair cell's transducer current carries information that allows the detection of vibrational amplitudes with an accuracy on the order of nanometers. We identify the transducer channel's molecular gating force as the physical factor controlling this accuracy in proportion to the inverse of its magnitude. Further, we show that the match of stochastic channel noise to gating-spring noise implies that the gating apparatus operates at the threshold of negative stiffness

Usher syndrome IIIA gene clarin-1 is essential for hair cell function and associated neural activation†

Usher syndrome 3A (USH3A) is an autosomal recessive disorder characterized by progressive loss of hearing and vision due to mutation in the clarin-1 (CLRN1) gene. Lack of an animal model has hindered our ability to understand the function of CLRN1 and the pathophysiology associated with USH3A. Here we report for the first time a mouse model for ear disease in USH3A. Detailed evaluation of inner ear phenotype in the Clrn1 knockout mouse (Clrn1−/−) coupled with expression pattern of Clrn1 in the inner ear are presented here. Clrn1 was expressed as early as embryonic day 16.5 in the auditory and vestibular hair cells and associated ganglionic neurons, with its expression being higher in outer hair cells (OHCs) than inner hair cells. Clrn1−/− mice showed early onset hearing loss that rapidly progressed to severe levels. Two to three weeks after birth (P14–P21), Clrn1−/− mice showed elevated auditory-evoked brainstem response (ABR) thresholds and prolonged peak and interpeak latencies. By P21, ∼70% of Clrn1−/− mice had no detectable ABR and by P30 these mice were deaf. Distortion product otoacoustic emissions were not recordable from Clrn1−/− mice. Vestibular function in Clrn1−/− mice mirrored the cochlear phenotype, although it deteriorated more gradually than cochlear function. Disorganization of OHC stereocilia was seen as early as P2 and by P21 OHC loss was observed. In sum, hair cell dysfunction and prolonged peak latencies in vestibular and cochlear evoked potentials in Clrn1−/− mice strongly indicate that Clrn1 is necessary for hair cell function and associated neural activation