The cell biology of hearing

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Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 nullmutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss.deafness | sensory system | ion channel H earing and balance depend on the transduction of mechanical stimuli into electrical signals. Transduction involves activation of mechanically gated ion channels near the tips of the stereocilia, specialized microvilli that form the hair bundles that project from the surface of sensory hair cells (1). Stereocilia have a cytoskeletal core composed of tightly packed, cross-linked, and uniformly polarized actin filaments (2, 3). Stereociliary length is regulated to ensure the characteristic staircase-like structure of each bundle, whose overall size and shape depends on location along the sensory organ (4). In the mammalian cochlea, hair bundles usually include three rows of stereocilia coupled by several types of extracellular links (2, 5). The embryonic and postnatal development of the bundle involves elongation and thickening of stereocilia, as well as elimination of redundant stereocilia (4, 5).In the adult cochlea, the height of stereocilia within each row is similar, not only within a single hair bundle but also between the bundles of adjacent hair cells, indicating a sophisticated level of control over growth (5, 6). Stereociliary growth and maintenance involves actin-binding proteins such as espin (7,8), plastin (9), twinfilin 2 (10), gelsolin (11), and unconventional myosin motors including myosin XVa (12) and myosin IIIa (13). Currently, we do not have a complete molecular understanding of hair bundle structure or how its growth and maintenance are controlled. Recently, we showed that epidermal growth factor receptor pathway substrate 8 (Eps8) (14) is located ...

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2

Furness

Johnson

Manor

et al. 2013

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“…The best known function of microvilli is to massively increase membrane surface area of these tissues to promote solute exchange, although these protrusions may also allow cells to communicate with their extracellular surroundings (6). Stereocilia, on the other hand, are composed of several rows of protrusions with graded height forming a staircase-like structure on the apical surface of inner ear hair cells, which collectively function to sense sound waves (7,8). Despite clear morphological and functional differences, microvilli and stereocilia share certain features at the molecular level.…”

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confidence: 99%

Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

Weck

et al. 2017

Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.M icrovilli and stereocilia are both actin bundle-based, fingerlike protrusions found on apical surfaces of many epithelial cells (1). Microvilli line the apical surface of epithelial cells forming a densely packed structure known as the brush border in tube-like tissues, such as intestines, kidney, and lung (2-5). The best known function of microvilli is to massively increase membrane surface area of these tissues to promote solute exchange, although these protrusions may also allow cells to communicate with their extracellular surroundings (6). Stereocilia, on the other hand, are composed of several rows of protrusions with graded height forming a staircase-like structure on the apical surface of inner ear hair cells, which collectively function to sense sound waves (7,8). Despite clear morphological and functional differences, microvilli and stereocilia share certain features at the molecular level. For example, the packing and organization of microvilli and stereocilia both rely on homologous cadherin-based tip-link complexes that target to the distal ends of these protrusions (9, 10). Additionally, a set of homologous unconventional myosins-including Myo1, Myo3, Myo6, and Myo7-are shared by and critical for the development, maintenance, and functions of microvilli and stereocilia (1,11,12).This study focuses on Myo7b, an unconventional myosin enriched in the microvilli of transporting epithelial cells (11, 13). Myo7b is characterized by a pair of MyTH4-FERM tandems in its tail cargo-binding domain. In addition to Myo7b, Myo7a, Myo10, and Myo15a also contain one or two MyTH4-FERM tandems in their tail domains (14). A common property of MyTH4-FERM myosins is their involvement in the formation or elongation/stabilization of actin-bundle support...

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confidence: 99%

“…This process depends on the opening of mechanoelectrical transducer (MET) channels located at the tips of the shorter of pairs of adjacent stereocilia (1), which are specialized microvilli-like structures that form the hair bundles that project from the upper surface of hair cells (2,3). Deflection of hair bundles in the excitatory direction (i.e., toward the taller stereocilia) stretches specialized linkages, the tip-links, present between adjacent stereocilia (3)(4)(5), opening the MET channels. In hair cells from lower vertebrates, open MET channels reclose during constant stimuli via an initial fast adaptation mechanism followed by a much slower, myosin-based motor process, both of which are driven by Ca 2+ entry through the channel itself (6)(7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Calcium entry into stereocilia drives adaptation of the mechanoelectrical transducer current of mammalian cochlear hair cells

Corns

Johnson

Kros

et al. 2014

109

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Mechanotransduction in the auditory and vestibular systems depends on mechanosensitive ion channels in the stereociliary bundles that project from the apical surface of the sensory hair cells. In lower vertebrates, when the mechanoelectrical transducer (MET) channels are opened by movement of the bundle in the excitatory direction, Ca 2+ entry through the open MET channels causes adaptation, rapidly reducing their open probability and resetting their operating range. It remains uncertain whether such Ca 2+ -dependent adaptation is also present in mammalian hair cells. Hair bundles of both outer and inner hair cells from mice were deflected by using sinewave or step mechanical stimuli applied using a piezo-driven fluid jet. We found that when cochlear hair cells were depolarized near the Ca 2+ reversal potential or their hair bundles were exposed to the in vivo endolymphatic Ca 2+ concentration (40 μM), all manifestations of adaptation, including the rapid decline of the MET current and the reduction of the available resting MET current, were abolished. MET channel adaptation was also reduced or removed when the intracellular Ca 2+ buffer 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) was increased from a concentration of 0.1 to 10 mM. The findings show that MET current adaptation in mouse auditory hair cells is modulated similarly by extracellular Ca 2+ , intracellular Ca 2+ buffering, and membrane potential, by their common effect on intracellular free Ca 2+ .H earing and balance depend on the transduction of mechanical stimuli into electrical signals. This process depends on the opening of mechanoelectrical transducer (MET) channels located at the tips of the shorter of pairs of adjacent stereocilia (1), which are specialized microvilli-like structures that form the hair bundles that project from the upper surface of hair cells (2,3). Deflection of hair bundles in the excitatory direction (i.e., toward the taller stereocilia) stretches specialized linkages, the tip-links, present between adjacent stereocilia (3-5), opening the MET channels. In hair cells from lower vertebrates, open MET channels reclose during constant stimuli via an initial fast adaptation mechanism followed by a much slower, myosin-based motor process, both of which are driven by Ca 2+ entry through the channel itself (6-13). In mammalian auditory hair cells, MET current adaptation seems to be mainly driven by the fast mechanism (14-16), although the exact process by which it occurs is still largely unknown. The submillisecond speed associated with the adaptation kinetics of the MET channels in rat and mouse cochlear hair cells (17,18) indicates that Ca 2+ , to cause adaptation, has to interact directly with a binding site on the channel or via an accessory protein (16). However, a recent investigation on rat auditory hair cells has challenged the view that Ca 2+ entry is required for fast adaptation, and instead proposed an as-yetundefined mechanism involving a Ca 2+ -independent reduction in the viscoelastic force of ele...