title: Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells.
abstract: Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.
authors: GIGA-Neurosciences, Developmental Neurobiology Unit, University of Liège, C.H.U. B36, Liège B-4000, Belgium.
authors: Jean
authors: J
authors: Defourny
authors: Anne-Lise
authors: AL
authors: Poirrier
authors: François
authors: F
authors: Lallemend
authors: Susana
authors: S
authors: Mateo Sánchez
authors: Jakob
authors: J
authors: Neef
authors: Pierre
authors: P
authors: Vanderhaeghen
authors: Eduardo
authors: E
authors: Soriano
authors: Christiane
authors: C
authors: Peuckert
authors: Klas
authors: K
authors: Kullander
authors: Bernd
authors: B
authors: Fritzsch
authors: Laurent
authors: L
authors: Nguyen
authors: Gustave
authors: G
authors: Moonen
authors: Tobias
authors: T
authors: Moser
authors: Brigitte
authors: B
authors: Malgrange
mesh_terms: D000344:Afferent Pathways / Q000378:metabolism*; D000818:Animals; D001309:Auditory Threshold; D036386:Ephrin-A5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020439:Growth Cones / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013136:Spiral Ganglion / Q000166:cytology / Q000294:innervation / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D036386:Ephrin-A5; D036122:Receptor, EphA4
references: Neuron. 1996 Jul;17(1):9-19
references: 8755474
references: J Comp Neurol. 2003 Jul 14;462(1):90-100
references: 12761826
references: Neuron. 2012 Jan 12;73(1):49-63
references: 22243746
references: Hear Res. 1986;24(1):17-36
references: 3759672
references: Curr Opin Neurobiol. 2006 Feb;16(1):59-66
references: 16417998
references: J Neurosci. 2007 May 9;27(19):5127-38
references: 17494698
references: Neuron. 2000 Dec;28(3):857-72
references: 11163272
references: Neuroreport. 1994 Jun 27;5(11):1309-12
references: 7919186
references: Am J Otolaryngol. 1985 Nov-Dec;6(6):453-67
references: 3909832
references: Science. 1982 Jul 9;217(4555):175-7
references: 7089553
references: Nat Commun. 2011 Feb 15;2:201
references: 21326233
references: Neuron. 2011 Jul 14;71(1):1-3
references: 21745632
references: J Comp Neurol. 2002 Jul 29;449(3):207-16
references: 12115675
references: Curr Opin Neurobiol. 2003 Aug;13(4):452-8
references: 12965293
references: Neuron. 1998 Feb;20(2):235-43
references: 9491985
references: Nat Protoc. 2007;2(5):1216-24
references: 17546017
references: Neuron. 1995 Jun;14(6):1153-64
references: 7605630
references: Dev Neurobiol. 2008 Sep 1;68(10):1269-86
references: 18563700
references: J Cell Biol. 2000 Apr 17;149(2):263-70
references: 10769020
references: J Neurosci. 2007 Jun 13;27(24):6442-51
references: 17567805
references: Development. 1992 Dec;116(4):1137-50
references: 1295734
references: Hear Res. 2011 Aug;278(1-2):43-51
references: 21329751
references: Neuron. 2000 Mar;25(3):563-74
references: 10774725
references: Nat Neurosci. 2004 Jan;7(1):33-40
references: 14699416
references: Neuroscience. 2007 Nov 30;150(1):212-22
references: 17964735
references: Ann Otol Rhinol Laryngol. 1981 Mar-Apr;90(2 Pt 1):158-60
references: 6164331
references: Neuron. 2003 Jul 31;39(3):453-65
references: 12895420
references: Am J Physiol Cell Physiol. 2011 Oct;301(4):C750-61
references: 21753183
references: Hear Res. 2008 Jan;235(1-2):39-46
references: 17967521
references: J Neurosci. 2007 Dec 19;27(51):14078-88
references: 18094247
references: J Biol Chem. 2007 Jul 6;282(27):19619-28
references: 17449913
references: J Neurobiol. 2004 Mar;58(4):479-92
references: 14978725
references: Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6324-7
references: 1631126
references: J Neurosci. 2009 Nov 11;29(45):14077-85
references: 19906956
references: Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):19060-5
references: 22065784
references: Cell. 1995 Aug 11;82(3):371-81
references: 7634327
references: Nat Neurosci. 2004 May;7(5):501-9
references: 15107857
references: Hear Res. 2000 Jan;139(1-2):42-50
references: 10601711
references: J Neurosci. 2008 Feb 20;28(8):1798-803
references: 18287496
references: Neuron. 2005 Apr 21;46(2):191-204
references: 15848799
references: J Neurosci. 2004 Mar 10;24(10):2542-50
references: 15014130
references: Neuron. 2011 Jul 14;71(1):76-91
references: 21745639
references: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9815-9
references: 7568224
references: Development. 2007 Aug;134(16):2925-33
references: 17626062
references: Acta Otolaryngol Suppl. 1985;421:31-40
references: 3898709
references: J Comp Neurol. 1990 Nov 15;301(3):443-60
references: 2262601
references: Cell. 2005 Apr 8;121(1):127-39
references: 15820684
references: J Neurosci. 2010 Jun 2;30(22):7587-97
references: 20519533
references: Brain Res. 1998 Sep 14;805(1-2):181-90
references: 9733963
references: Prog Brain Res. 2004;146:265-78
references: 14699969
references: Hear Res. 1996 Apr;93(1-2):52-71
references: 8735068
references: Nat Rev Neurosci. 2010 Dec;11(12):812-22
references: 21045860
references: J Neurosci. 1996 Dec 1;16(23):7649-60
references: 8922421
references: Cell Tissue Res. 1997 Jan;287(1):23-41
references: 9011399
references: J Neurobiol. 2004 Apr;59(1):134-46
references: 15007832
references: Oncogene. 1996 Apr 18;12(8):1727-36
references: 8622893
references: Dev Biol. 1996 Nov 1;179(2):382-401
references: 8903354
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5329-34
references: 9560275
references: Nat Neurosci. 2006 Mar;9(3):322-30
references: 16491080