Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin alpha8beta1.
The mammalian inner ear contains organs for the detection of sound and acceleration, the cochlea and the vestibule, respectively. Mechanosensory hair cells within the neuroepithelia of these organs transduce mechanical force generated by sound waves or head movements into neuronal signals. Defects in hair cells lead to deafness and balance defects. Hair cells have stereocilia that are indispensable for mechanosensation, but the molecular mechanisms regulating stereocilia formation are poorly understood. We show here that integrin alpha8beta1, its ligand fibronectin and the integrin-regulated focal adhesion kinase (FAK) co-localize to the apical hair-cell surface where stereocilia are forming. In mice homozygous for a targeted mutation of Itga8 (encoding the alphabeta8 subunit), this co-localization is perturbed and hair cells in the utricle, a vestibular subcompartment, lack stereocilia or contain malformed stereocilia. Most integrin alpha-8beta1-deficient mice die soon after birth due to kidney defects. Many of the survivors have difficulty balancing, consistent with the structural defects of the inner ear. Our data suggest that integrin alpha8beta1, and potentially other integrins, regulates hair-cell differentiation and stereocilia maturation. Mutations affecting matrix molecules cause inherited forms of inner ear disease and integrins may mediate some effects of matrix molecules in the ear; thus, mutations in integrin genes may lead to inner-ear diseases as well.
Littlewood Evans
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A
Friedrich Miescher Institute, Basel, Switzerland.
Müller
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U
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000831:Animals, Newborn; D064032:Calbindin 2; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002452:Cell Count; D002923:Cilia / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006198:Hair Cells, Auditory / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016023:Integrins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009218:Myosins / Q000096:biosynthesis; D004856:Postural Balance; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D012444:Saccule and Utricle / Q000196:embryology / Q000473:pathology; D012678:Sensation Disorders / Q000235:genetics
D000199:Actins; D064032:Calbindin 2; D015815:Cell Adhesion Molecules; D016023:Integrins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C094866:integrin alpha8beta1; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D009218:Myosins