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The Journal of Neuroscience, June 13, 2007, 27(24):6478-6488; doi:10.1523/JNEUROSCI.0342-07.2007

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Cellular/Molecular
Molecular Characterization of the Ankle-Link Complex in Cochlear Hair Cells and Its Role in the Hair Bundle Functioning

Nicolas Michalski,^1 * Vincent Michel,^1 * Amel Bahloul,¹ Gaëlle Lefèvre,¹ Jérémie Barral,³ Hideshi Yagi,² Sébastien Chardenoux,¹ Dominique Weil,¹ Pascal Martin,³ Jean-Pierre Hardelin,¹ Makoto Sato,² and Christine Petit¹

¹Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 587, Collège de France, Institut Pasteur, 75724 Paris cedex 15, France, ²Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Research and Education Program for Life Science, University of Fukui, Eiheiji, Fukui 910-1193, Japan, and ³Centre National de la Recherche Scientifique Unité Mixte de Recherche 168, Institut Curie, 75248 Paris cedex 05, France

Correspondence should be addressed to Christine Petit, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 587, Unité de Génétique des Déficits Sensoriels, Collège de France, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France. Email: cpetit{at}pasteur.fr

Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. Here, we show that the transmembrane protein usherin, the putative transmembrane protein vezatin, and the PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-containing submembrane protein whirlin are colocalized with Vlgr1 at the stereocilia base in developing cochlear hair cells and are absent in Vlgr1^–/– mice that lack the ankle links. Direct in vitro interactions between these four proteins further support their involvement in a molecular complex associated with the ankle links and scaffolded by whirlin. In addition, the delocalization of these proteins in myosin VIIa defective mutant mice as well as the myosin VIIa tail direct interactions with vezatin, whirlin, and, we show, Vlgr1 and usherin, suggest that myosin VIIa conveys proteins of the ankle-link complex to the stereocilia. Adenylyl cyclase 6, which was found at the base of stereocilia, was both overexpressed and mislocated in Vlgr1^–/– mice. In postnatal day 7 Vlgr1^–/– mice, mechanoelectrical transduction currents evoked by displacements of the hair bundle toward the tallest stereocilia (i.e., in the excitatory direction) were reduced in outer but not inner hair cells. In both cell types, stimulation of the hair bundle in the opposite direction paradoxically resulted in significant transduction currents. The absence of ankle-link-mediated cohesive forces within hair bundles lacking Vlgr1 may account for the electrophysiological results. However, because some long cadherin-23 isoforms could no longer be detected in Vlgr1^–/– mice shortly after birth, the loss of some apical links could be involved too. The premature disappearance of these cadherin isoforms in the Vlgr1^–/– mutant argues in favor of a signaling function of the ankle links in hair bundle differentiation.

Key words: cochlea; hair bundle; ankle link; Vlgr1; adenylyl cyclase 6; Usher syndrome

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Received Jan. 25, 2007; revised May 2, 2007; accepted May 10, 2007.

Correspondence should be addressed to Christine Petit, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 587, Unité de Génétique des Déficits Sensoriels, Collège de France, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France. Email: cpetit{at}pasteur.fr

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