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Genetics of auditory mechano-electrical transduction.

Michalski N, Petit C - Pflugers Arch. (2014)

Bottom Line: The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea.The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks.Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing.

View Article: PubMed Central - PubMed

Affiliation: Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France, nicolas.michalski@pasteur.fr.

ABSTRACT
The hair bundles of cochlear hair cells play a central role in the auditory mechano-electrical transduction (MET) process. The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea. In contrast, human and mouse genetics have proven to be particularly powerful. The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks. Notably, MET relies not only on the MET machinery but also on several elements ensuring the proper sound-induced oscillation of the hair bundle or the ionic environment necessary to drive the MET current. Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing.

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List of myosins and their interactors involved in the control of stereocilia length. The roles of myosin-VI, myosin-VIIa, and myosin-XV have been determined by the study of mutant mice defective for these proteins. In contrast, the implication of myosin-IIIa in stereocilia elongation was assessed in vitro from the observation that stereocilia are taller than normal in co-transfected hair cells producing myosin-IIIa and espin 1 [184]. Single asterisk These proteins have not been associated with deafness forms in humans or in mice
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Fig4: List of myosins and their interactors involved in the control of stereocilia length. The roles of myosin-VI, myosin-VIIa, and myosin-XV have been determined by the study of mutant mice defective for these proteins. In contrast, the implication of myosin-IIIa in stereocilia elongation was assessed in vitro from the observation that stereocilia are taller than normal in co-transfected hair cells producing myosin-IIIa and espin 1 [184]. Single asterisk These proteins have not been associated with deafness forms in humans or in mice

Mentions: The hair bundle also contains various unconventional myosins. Their respective contributions in molecular transport and in the maintenance of mechanical tension have not yet been clarified. Myosins are logical candidates to transport proteins along the stereocilia dense network of actin filaments [209]. Moreover, their presence at different locations, especially near the tip or at the base of stereocilia, may exert tension on actin filaments and modify stereocilia shape. The study of myosin-IIIa, myosin-VI, myosin-VIIa and myosin-XV has provided additional information about the molecular complexes involved in the maintenance of the stereocilia actin cores (Fig. 4). Myosin-IIIa [222] accumulates at stereocilia tips [188, 223] and promotes stereocilia lengthening when overexpressed with espin-1 in hair cells [184]. Stereocilia grow excessively and fuse together in mutant mice deficient for myosin-VI [14, 13, 193]. It has recently been proposed that myosin-VI participates in a molecular complex with CLIC5, PTPRQ, radixin and taperin, which are all present at the base of stereocilia [183, 70]. This complex may help to stabilise interactions between the plasma membrane and the subcortical actin cytoskeleton, which may explain the fusion of stereocilia in myosin-VI-deficient mice [182, 183]. Nonetheless, the mechanism of stereocilia overgrowth in these mice is still poorly understood. The tallest row of stereocilia in mutant mice deficient for myosin-VIIa is also abnormally long [167] (Fig. 2c). This phenotype has been ascribed to the concomitant loss of twinfilin-2, an actin-sequestering and actin-capping protein that inhibits actin polymerisation [178, 159]. Another molecular complex was uncovered by the observation of abnormally short stereocilia in myosin-XV-defective [165] and whirlin-defective mouse mutants [134] (Fig. 2c). Myosin-XV and whirlin interact and form a complex with eps8 that plays a crucial role in the elongation of the stereocilia actin filaments [50, 21, 127]. This complex also includes the membrane-associated guanylate kinase (MAGUK) p55, protein 4.1R [133] and gelsolin, which is an actin-capping and actin-severing protein [135]. Therefore, several myosin-dependent molecular complexes that are linked to actin dynamics work in concert to determine stereocilia length.Fig. 4


Genetics of auditory mechano-electrical transduction.

Michalski N, Petit C - Pflugers Arch. (2014)

List of myosins and their interactors involved in the control of stereocilia length. The roles of myosin-VI, myosin-VIIa, and myosin-XV have been determined by the study of mutant mice defective for these proteins. In contrast, the implication of myosin-IIIa in stereocilia elongation was assessed in vitro from the observation that stereocilia are taller than normal in co-transfected hair cells producing myosin-IIIa and espin 1 [184]. Single asterisk These proteins have not been associated with deafness forms in humans or in mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4281357&req=5

Fig4: List of myosins and their interactors involved in the control of stereocilia length. The roles of myosin-VI, myosin-VIIa, and myosin-XV have been determined by the study of mutant mice defective for these proteins. In contrast, the implication of myosin-IIIa in stereocilia elongation was assessed in vitro from the observation that stereocilia are taller than normal in co-transfected hair cells producing myosin-IIIa and espin 1 [184]. Single asterisk These proteins have not been associated with deafness forms in humans or in mice
Mentions: The hair bundle also contains various unconventional myosins. Their respective contributions in molecular transport and in the maintenance of mechanical tension have not yet been clarified. Myosins are logical candidates to transport proteins along the stereocilia dense network of actin filaments [209]. Moreover, their presence at different locations, especially near the tip or at the base of stereocilia, may exert tension on actin filaments and modify stereocilia shape. The study of myosin-IIIa, myosin-VI, myosin-VIIa and myosin-XV has provided additional information about the molecular complexes involved in the maintenance of the stereocilia actin cores (Fig. 4). Myosin-IIIa [222] accumulates at stereocilia tips [188, 223] and promotes stereocilia lengthening when overexpressed with espin-1 in hair cells [184]. Stereocilia grow excessively and fuse together in mutant mice deficient for myosin-VI [14, 13, 193]. It has recently been proposed that myosin-VI participates in a molecular complex with CLIC5, PTPRQ, radixin and taperin, which are all present at the base of stereocilia [183, 70]. This complex may help to stabilise interactions between the plasma membrane and the subcortical actin cytoskeleton, which may explain the fusion of stereocilia in myosin-VI-deficient mice [182, 183]. Nonetheless, the mechanism of stereocilia overgrowth in these mice is still poorly understood. The tallest row of stereocilia in mutant mice deficient for myosin-VIIa is also abnormally long [167] (Fig. 2c). This phenotype has been ascribed to the concomitant loss of twinfilin-2, an actin-sequestering and actin-capping protein that inhibits actin polymerisation [178, 159]. Another molecular complex was uncovered by the observation of abnormally short stereocilia in myosin-XV-defective [165] and whirlin-defective mouse mutants [134] (Fig. 2c). Myosin-XV and whirlin interact and form a complex with eps8 that plays a crucial role in the elongation of the stereocilia actin filaments [50, 21, 127]. This complex also includes the membrane-associated guanylate kinase (MAGUK) p55, protein 4.1R [133] and gelsolin, which is an actin-capping and actin-severing protein [135]. Therefore, several myosin-dependent molecular complexes that are linked to actin dynamics work in concert to determine stereocilia length.Fig. 4

Bottom Line: The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea.The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks.Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing.

View Article: PubMed Central - PubMed

Affiliation: Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France, nicolas.michalski@pasteur.fr.

ABSTRACT
The hair bundles of cochlear hair cells play a central role in the auditory mechano-electrical transduction (MET) process. The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea. In contrast, human and mouse genetics have proven to be particularly powerful. The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks. Notably, MET relies not only on the MET machinery but also on several elements ensuring the proper sound-induced oscillation of the hair bundle or the ionic environment necessary to drive the MET current. Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing.

Show MeSH