title: β-Actin and fascin-2 cooperate to maintain stereocilia length.
abstract: Stereocilia are actin-based protrusions on auditory sensory hair cells that are deflected by sound waves to initiate the conversion of mechanical energy to neuronal signals. Stereocilia maintenance is essential because auditory hair cells are not renewed in mammals. This process requires both β-actin and γ-actin as knock-out mice lacking either isoform develop distinct stereocilia pathology during aging. In addition, stereocilia integrity may hinge on immobilizing actin, which outside of a small region at stereocilia tips turns over with a very slow, months-long half-life. Here, we establish that β-actin and the actin crosslinking protein fascin-2 cooperate to maintain stereocilia length and auditory function. We observed that mice expressing mutant fascin-2 (p.R109H) or mice lacking β-actin share a common phenotype including progressive, high-frequency hearing loss together with shortening of a defined subset of stereocilia in the hair cell bundle. Fascin-2 binds β-actin and γ-actin filaments with similar affinity in vitro and fascin-2 does not depend on β-actin for localization in vivo. Nevertheless, double-mutant mice lacking β-actin and expressing fascin-2 p.R109H have a more severe phenotype suggesting that each protein has a different function in a common stereocilia maintenance pathway. Because the fascin-2 p.R109H mutant binds but fails to efficiently crosslink actin filaments, we propose that fascin-2 crosslinks function to slow actin depolymerization at stereocilia tips to maintain stereocilia length.
authors: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA. perrin@umn.edu
authors: Benjamin J
authors: BJ
authors: Perrin
authors: Dana M
authors: DM
authors: Strandjord
authors: Praveena
authors: P
authors: Narayanan
authors: Davin M
authors: DM
authors: Henderson
authors: Kenneth R
authors: KR
authors: Johnson
authors: James M
authors: JM
authors: Ervasti
mesh_terms: D000161:Acoustic Stimulation; D000199:Actins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics; D000818:Animals; D001572:Benzofurans; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004569:Electroencephalography; D047628:Estrogen Receptor alpha / Q000235:genetics; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics / Q000502:physiology; D005260:Female; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D006316:Hearing Loss, High-Frequency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D011804:Quinolines; D059547:Stereocilia / Q000502:physiology* / Q000648:ultrastructure
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D000199:Actins; D001572:Benzofurans; D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D047628:Estrogen Receptor alpha; D008840:Microfilament Proteins; D011804:Quinolines; C020324:fascin
references: Nature. 2007 Sep 6;449(7158):87-91
references: 17805295
references: Genomics. 2000 Apr 15;65(2):146-56
references: 10783262
references: J Biol Chem. 2011 Aug 26;286(34):30087-96
references: 21685497
references: PLoS One. 2009 Sep 23;4(9):e7097
references: 19774077
references: J Biol Chem. 2010 May 21;285(21):16087-95
references: 20308063
references: PLoS Genet. 2010 Oct 14;6(10):e1001158
references: 20976199
references: Bioarchitecture. 2011 Jul;1(4):169-174
references: 22069509
references: Genomics. 2008 Oct;92(4):219-25
references: 18662770
references: Nature. 2009 Jan 22;457(7228):441-5
references: 19158791
references: Mol Biol Cell. 2003 Oct;14(10):3953-66
references: 14517310
references: Nature. 2002 Aug 22;418(6900):837-8
references: 12192399
references: J Neurosci. 2010 Jul 21;30(29):9683-94
references: 20660251
references: J Cell Biol. 2004 Mar 15;164(6):887-97
references: 15024034
references: Cell. 2012 Dec 7;151(6):1283-95
references: 23217710
references: Dev Biol. 2002 Apr 15;244(2):305-18
references: 11944939
references: J Cell Biol. 2003 Dec 8;163(5):1045-55
references: 14657236
references: Genomics. 2005 Sep;86(3):259-70
references: 16039824
references: Brain Res. 2009 Jun 24;1277:42-51
references: 19236853
references: Nat Cell Biol. 2009 Apr;11(4):443-50
references: 19287378
references: J Cell Sci. 2011 Oct 1;124(Pt 19):3305-18
references: 21940796
references: Dev Dyn. 2005 Nov;234(3):633-50
references: 16145671
references: Biochemistry. 1999 Nov 9;38(45):14860-7
references: 10555968
references: J Neurosci. 2009 Dec 2;29(48):15083-8
references: 19955359
references: J Mol Biol. 2010 Jul 16;400(3):589-604
references: 20434460
references: Nature. 2010 Oct 7;467(7316):724-8
references: 20844487
references: Hear Res. 2004 Feb;188(1-2):21-8
references: 14759567
references: Nat Neurosci. 2013 Mar;16(3):365-74
references: 23334578
references: J Struct Biol. 2011 Feb;173(2):350-7
references: 20832473
references: Mol Biol Cell. 2011 Nov;22(21):4047-58
references: 21900491
references: Nat Genet. 2003 Sep;35(1):21-3
references: 12910270
references: Nature. 2012 Jan 15;481(7382):520-4
references: 22246323
references: Mol Cell Biol. 2008 Mar;28(5):1702-12
references: 18160714
references: Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9703-8
references: 19497859
references: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5825-30
references: 21436032
references: Nat Neurosci. 2009 May;12(5):553-8
references: 19330002
references: Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1380-8
references: 17325187
references: Nat Cell Biol. 2005 Feb;7(2):148-56
references: 15654330