title: Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly.
abstract: Defects in myosin XVa and the PDZ domain-containing protein, whirlin, underlie deafness in humans and mice. Hair bundles of mutant mice defective for either protein have abnormally short stereocilia. Here, we show that whirlin, like myosin XVa, is present at the very tip of each stereocilium in the developing and mature hair bundles of the cochlear and vestibular system. We found that myosin XVa SH3-MyTH4 region binds to the short isoform of whirlin (PR-PDZ3) that can rescue the stereocilia growth defect in whirlin defective mice. Moreover, the C-terminal MyTH4-FERM region of myosin XVa binds to the PDZ1 and PDZ2 domains of the long whirlin isoform. We conclude that a direct myosin XVa-whirlin interaction at the stereocilia tip is likely to control the elongation of stereocilia. Whirlin, unlike myosin XVa, is also transiently localized in the basal region of developing stereocilia in rat vestibular and cochlear hair cells until P4 and P12, respectively. Notably, whirlin also interacts with myosin VIIa that is present along the entire length of the stereocilia. Finally, we show that the transmembrane netrin-G1 ligand (NGL-1) binds to the PDZ1 and PDZ2 domains of whirlin and has an extracellular region that homophilically self-interacts in a Ca2+-dependent manner. The interaction between whirlin and NGL-1 might be involved in the stabilization of interstereociliar links.
authors.affiliation: Unité de Génétique des Déficits Sensoriels, INSERM U587, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, cedex 15, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Delprat
authors.forename: Vincent
authors.initials: V
authors.lastname: Michel
authors.forename: Richard
authors.initials: R
authors.lastname: Goodyear
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Nicolas
authors.initials: N
authors.lastname: Michalski
authors.forename: Aziz
authors.initials: A
authors.lastname: El-Amraoui
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perfettini
authors.forename: Pierre
authors.initials: P
authors.lastname: Legrain
authors.forename: Guy
authors.initials: G
authors.lastname: Richardson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D000199:Actins; D008565:Membrane Proteins; C114013:Myo15 protein, mouse; D009419:Nerve Tissue Proteins; C477218:Whrn protein, mouse; D009218:Myosins