title: Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia.
abstract: The mechanotransducer channels of auditory hair cells are gated by tip-links, oblique filaments that interconnect the stereocilia of the hair bundle. Tip-links stretch from the tips of stereocilia in the short and middle rows to the sides of neighboring, taller stereocilia. They are made of cadherin-23 and protocadherin-15, products of the Usher syndrome type 1 genes USH1D and USH1F, respectively. In this study we address the role of sans, a putative scaffold protein and product of the USH1G gene. In Ush1g(-/-) mice, the cohesion of stereocilia is disrupted, and both the amplitude and the sensitivity of the transduction currents are reduced. In Ush1g(fl/fl)Myo15-cre(+/-) mice, the loss of sans occurs postnatally and the stereocilia remain cohesive. In these mice, there is a decrease in the amplitude of the total transducer current with no loss in sensitivity, and the tips of the stereocilia in the short and middle rows lose their prolate shape, features that can be attributed to the loss of tip-links. Furthermore, stereocilia from these rows undergo a dramatic reduction in length, suggesting that the mechanotransduction machinery has a positive effect on F-actin polymerization. Sans interacts with the cytoplasmic domains of cadherin-23 and protocadherin-15 in vitro and is absent from the hair bundle in mice defective for either of the two cadherins. Because sans localizes mainly to the tips of short- and middle-row stereocilia in vivo, we conclude that it belongs to a molecular complex at the lower end of the tip-link and plays a critical role in the maintenance of this link.
authors: Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75724 Paris cedex 15, France.
authors: Elisa
authors: E
authors: Caberlotto
authors: Vincent
authors: V
authors: Michel
authors: Isabelle
authors: I
authors: Foucher
authors: Amel
authors: A
authors: Bahloul
authors: Richard J
authors: RJ
authors: Goodyear
authors: Elise
authors: E
authors: Pepermans
authors: Nicolas
authors: N
authors: Michalski
authors: Isabelle
authors: I
authors: Perfettini
authors: Olinda
authors: O
authors: Alegria-Prévot
authors: Sébastien
authors: S
authors: Chardenoux
authors: Marcio
authors: M
authors: Do Cruzeiro
authors: Jean-Pierre
authors: JP
authors: Hardelin
authors: Guy P
authors: GP
authors: Richardson
authors: Paul
authors: P
authors: Avan
authors: Dominique
authors: D
authors: Weil
authors: Christine
authors: C
authors: Petit
mesh_terms: D000199:Actins / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058105:Polymerization; D011498:Protein Precursors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C499091:Cdh23 protein, mouse; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; C477451:Sans protein, mouse