Eps8 Regulates Hair Bundle Length and Functional Maturation of Mammalian Auditory Hair Cells

Zampini, Valeria; Rüttiger, Lukas; Johnson, Stuart L.; Franz, Christoph; Furness, David N.; Waldhaus, Jörg; Xiong, Hao; Hackney, Carole M.; Holley, Matthew C.; Offenhäuser, Nina; Fiore, Pier Paolo Di; Knipper, Marlies; Masetto, Sergio; Marcotti, Walter

doi:10.1371/journal.pbio.1001048

Cited by 111 publications

(178 citation statements)

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“…S2). The distribution of Eps8L2 overlapped with that of Eps8 (15,16) as previously suggested in other systems (17). However, the spatiotemporal expression patterns in cochlear hair cells were different.…”

Section: Resultssupporting

confidence: 82%

“…Despite the similar expression profile and high homology of the two genes (17), there is very little functional redundancy between the two proteins in cochlear hair cells. Although the localization of Eps8 requires the motor protein myosin XVa (15,16), we found that in shaker-2 mice, which are deficient in myosin XVa (18), Eps8L2 was still present at the stereocilia tip (Fig. 1F).…”

Section: Resultsmentioning

confidence: 92%

“…We studied the basolateral membrane properties in hair cells from Eps8L2 KO mice to determine whether the loss of auditory function was associated with abnormalities in basolateral membrane properties, as previously seen in the absence of Eps8 (16). These studies revealed no differences in the K + currents in control and Eps8L2 KO IHCs at P18 and P96, the expression of the motor protein prestin in P135 OHCs (Fig.…”

Section: Mechanotransducer Currents and Basolateral Membrane Propertimentioning

confidence: 80%

“…1E), which are short and show a relatively similar height among rows (15,16). Despite the similar expression profile and high homology of the two genes (17), there is very little functional redundancy between the two proteins in cochlear hair cells.…”

Section: Resultsmentioning

confidence: 98%

“…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 at the tips of stereocilia where it regulates normal growth of the hair bundle (15,16). In mammals, the Eps8 family includes three Eps8-related proteins named Eps8L1-L3.…”

mentioning

confidence: 99%

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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

Proc. Natl. Acad. Sci. U.S.A.

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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 ...

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 92%

Section: Mechanotransducer Currents and Basolateral Membrane Propertimentioning

confidence: 80%

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

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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

Proc. Natl. Acad. Sci. U.S.A.

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Espin overexpression causes stereocilia defects and provides an anti‐capping effect on actin polymerization

et al. 2022

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Stereocilia are actin-based projections of hair cells that are arranged in a step like array, in rows of increasing height, and that constitute the mechanosensory organelle used for the senses of hearing and balance. In order to function properly, stereocilia must attain precise sizes in different hair cell types and must coordinately form distinct rows with varying lengths. Espins are actin-bundling proteins that have a wellcharacterized role in stereocilia formation; loss of function mutations in Espin result in shorter stereocilia and deafness in the jerker mouse. Here we describe the generation of an Espin overexpressing transgenic mouse line that results in longer first row stereocilia and discoordination of second-row stereocilia length. Furthermore, Espin overexpression results in the misregulation of other stereocilia factors including GNAI3, GPSM2, EPS8, WHRN, and MYO15A, revealing that GNAI3 and GPSM2 are dispensable for stereocilia overgrowth. Finally, using an in vitro actin polymerization assay we show that espin provides an anti-capping function that requires both the Gactin binding WH2 domain as well as either the C-terminal F-actin binding domain or the internal xAB actin-binding domain. Our results provide a novel function for Espins at the barbed ends of actin filaments distinct from its previous known function of actin bundling that may account for their effects on stereocilia growth.

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Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

et al. 2016

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Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.

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Eps8 Regulates Hair Bundle Length and Functional Maturation of Mammalian Auditory Hair Cells

Cited by 111 publications

References 81 publications

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

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

Espin overexpression causes stereocilia defects and provides an anti‐capping effect on actin polymerization

Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

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