The tip-link molecular complex of the auditory mechano-electrical transduction machinery

Pepermans, Elise; Petit, Christine

doi:10.1016/j.heares.2015.05.005

Cited by 35 publications

(40 citation statements)

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“…In developing hair cells, the stereocilia of the hair bundle are connected to each other, and some are connected to the kinocilium. Five different types of extracellular lateral links have been identified: early transient lateral links, kinociliary links, shaft links, ankle links, and the tip-link El-Amraoui and Petit 2014;Pepermans and Petit 2015;Michalski and Petit 2015;Fig. 13.2d).…”

Section: The Sound-receptive Structure Of Hair Cells the Hair Bundlementioning

confidence: 99%

“…Usher syndrome has an estimated prevalence of 1/10,000, and seems to account for about 50 % of all cases of monogenic deafness/blindness. USH1, the most severe form, is characterised by severe to profound congenital deafness, constant vestibular dysfunction, and retinitis pigmentosa beginning before puberty, eventually leading to blindness (reviewed by El-Amraoui and Petit 2014; Mathur and Yang 2015;Pepermans and Petit 2015). Six USH1 genes have been identified; they encode the actin-based motor protein myosin VIIa (USH1B), the PDZ-domain-containing submembrane protein harmonin (USH1C), the scaffold protein Sans (USH1G), the integrin and calcium-binding protein CIB2 (USH1J), and the two Ca 2þ -dependent adhesion proteins, cadherin-23 (USH1D) and protocadherin-15 (USH1F; reviewed by Petit and Richardson 2009;Pepermans and Petit 2015).…”

Section: Two Cadherin-related Proteins Form the Tip-link A Key Compomentioning

confidence: 99%

“…13.2e). An interdisciplinary study of these animal models, including an in-depth analysis of USH1 proteins, led to the suggestion that the physical coupling of cadherin-23-and protocadherin-15-mediated early transient interstereociliary and kinociliary links is required for the formation of individual, correctly shaped hair bundles (Boeda et al 2002;Lagziel et al 2005;Michel et al 2005;Siemens et al 2002, reviewed by El-Amraoui andMathur and Yang 2015;Richardson et al 2011;Pepermans and Petit 2015). The tip-link, which has a helical structure (Kachar et al 2000), consists of at least two cadherin heterodimers: cis-homodimers of cadherin-23 interact in trans with cis-homodimers of protocadherin-15 (Kazmierczak et al 2007), to form the upper and lower parts of this link (Fig.…”

Section: Two Cadherin-related Proteins Form the Tip-link A Key Compomentioning

confidence: 99%

“…The three integral membrane isoforms consist of 11 EC repeats, a single transmembrane domain, and a variable cytoplasmic domain carrying different C-terminal PDZ-binding motifs (PBMs). The various cytoplasmic regions of these protocadherin-15 transmembrane splice isoforms are encoded by different final coding exons: exon 35 for CD1, exon 38 for CD2, and exon 39 for CD3 (Ahmed et al 2008;Pepermans and Petit 2015). The different cytoplasmic domains probably impart functional specificity by conferring on the protein an ability to interact with different binding partners.…”

Section: Protocadherin-15 At the Core Of The Lower Tip-link Molecularmentioning

confidence: 99%

“…However, it remains unclear whether Tmc1, which persists in the mature hair bundle, unlike Tmc2, is a component of the pore channel (see Pepermans and Petit 2015). Two other transmembrane proteins located in the apical region of the stereocilia, and the absence of which leads to deafness, have been identified as key proteins of the MET machinery: Tmhs (tetraspan membrane protein of hair cell stereocilia; Xiong et al 2012) and Tmie (transmembrane protein of inner ear hair cells; Zhao et al 2014).…”

Section: Constructing the Tip-link Interactomementioning

confidence: 99%

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Cadherins in the Auditory Sensory Organ

El-Amraoui

Petit

2016

The Cadherin Superfamily

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The exquisite sensitivity and frequency tuning of hearing depend on the correct structure and functioning of the auditory sensory hair cells, the neighbouring supporting cells, and the homeostasis of their ionic environment. The increasing number of adhesion proteins identified as causing hearing impairment in humans and mice when defective is consistent with a critical role for cellcell junctions between neighbouring epithelial cells of the cochlea, and of fibrous links within the hair bundle, the sensory hair cell structure responsible for sound reception. Classical cadherins and/or associated adherens-junction proteins, such as p120-catenin or nectin 3, have been shown to be essential for establishment of the regular mosaic cellular pattern of the auditory sensory epithelium. Two cadherinrelated proteins, protocadherin-15 and cadherin-23, are key components of both lateral links and tip-links in hair bundles; they are essential components of the mechanoelectrical transduction machinery. Studies of the role of these adhesion proteins and of the pathogenesis of the forms of deafness caused by defects of these proteins have provided considerable insight into the development and functioning of the auditory sensory epithelium, and of the hair cells in particular.

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Section: The Sound-receptive Structure Of Hair Cells the Hair Bundlementioning

confidence: 99%

Section: Two Cadherin-related Proteins Form the Tip-link A Key Compomentioning

confidence: 99%

Section: Two Cadherin-related Proteins Form the Tip-link A Key Compomentioning

confidence: 99%

Section: Protocadherin-15 At the Core Of The Lower Tip-link Molecularmentioning

confidence: 99%

Section: Constructing the Tip-link Interactomementioning

confidence: 99%

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Cadherins in the Auditory Sensory Organ

El-Amraoui

Petit

2016

The Cadherin Superfamily

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Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

Mittal

Debs

Nguyen

et al. 2017

Journal Cellular Physiology

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Ear is a sensitive organ involved in hearing and balance function. The complex signaling network in the auditory system plays a crucial role in maintaining normal physiological function of the ear. The inner ear comprises a variety of host signaling pathways working in synergy to deliver clear sensory messages. Any disruption, as minor as it can be, has the potential to affect this finely tuned system with temporary or permanent sequelae including vestibular deficits and hearing loss. Mutations linked to auditory symptoms, whether inherited or acquired, are being actively researched for ways to reverse, silence, or suppress them. In this article, we discuss recent advancements in understanding the pathways involved in auditory system signaling, from hair cell development through transmission to cortical centers. Our review discusses Notch and Wnt signaling, cell to cell communication through connexin and pannexin channels, and the detrimental effects of reactive oxygen species on the auditory system. There has been an increased interest in the auditory community to explore the signaling system in the ear for hair cell regeneration. Understanding signaling pathways in the auditory system will pave the way for the novel avenues to regenerate sensory hair cells and restore hearing function. J. Cell. Physiol. 232: 2710-2721, 2017. © 2016 Wiley Periodicals, Inc.

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Developmental regulation of planar cell polarity and hair‐bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics

Sipe

2015

WIREs Developmental Biology

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Hearing loss is the most common and costly sensory defect in humans, and genetic causes underlie a significant proportion of affected individuals. In mammals, sound is detected by hair cells housed in the cochlea of the inner ear, whose function depends on a highly specialized mechanotransduction organelle, the hair bundle. Understanding the factors that regulate the development and functional maturation of the hair bundle is crucial for understanding the pathophysiology of human deafness. Genetic analysis of deafness genes in animal models, together with complementary forward genetic screens and conditional knock-out mutations in essential genes, have provided great insights into the molecular machinery underpinning hair bundle development and function. In this review, we highlight recent advances in our understanding of hair bundle morphogenesis, with an emphasis on the molecular pathways governing hair bundle polarity and orientation. We next discuss the proteins and structural elements important for hair cell mechanotransduction as well as hair bundle cohesion and maintenance. In addition, developmental signals thought to regulate tonotopic features of hair cells are introduced. Finally, novel approaches that complement classic genetics for studying the molecular etiology of human deafness are presented.

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The tip-link molecular complex of the auditory mechano-electrical transduction machinery

Cited by 35 publications

References 45 publications

Cadherins in the Auditory Sensory Organ

Cadherins in the Auditory Sensory Organ

Signaling in the Auditory System: Implications in Hair Cell Regeneration and Hearing Function

Developmental regulation of planar cell polarity and hair‐bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics

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