[en] 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.
Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells.
Publication date :
2013
Journal title :
Nature Communications
eISSN :
2041-1723
Publisher :
Nature Publishing Group, United Kingdom
Volume :
4
Pages :
1438
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique FRIA - Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture Fonds Léon Fredericq
Kiang, N. Y., Rho, J. M., Northrop, C. C., Liberman, M. C. & Ryugo, D. K. Hair-cell innervation by spiral ganglion cells in adult cats. Science 217, 175-177 (1982) (Pubitemid 12081423)
Spoendlin, H. Anatomy of cochlear innervation. Am. J. Otolaryngol. 6, 453-467 (1985) (Pubitemid 16197657)
Liberman, M. C. & Brown, M. C. Physiology and anatomy of single olivocochlear neurons in the cat. Hear. Res. 24, 17-36 (1986) (Pubitemid 16043859)
Strutz, J. Efferent innervation of the cochlea. Ann. Otol. Rhinol. Laryngol. 90, 158-160 (1981) (Pubitemid 11157164)
Huang, L. C., Thorne, P. R., Housley, G. D. & Montgomery, J. M. Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea. Development 134, 2925-2933 (2007) (Pubitemid 47386905)
Defourny, J., Lallemend, F. & Malgrange, B. Structure and development of cochlear afferent innervation in mammals. Am. J. Physiol. Cell Physiol. 301, C750-C761 (2011)
Cheng, H. J., Nakamoto, M., Bergemann, A. D. & Flanagan, J. G. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371-381 (1995)
Flanagan, J. G. Neural map specification by gradients. Curr. Opin. Neurobiol. 16, 59-66 (2006) (Pubitemid 43221854)
Frisen, J. et al. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235-243 (1998) (Pubitemid 28125068)
Gale, N. W. et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9-19 (1996) (Pubitemid 26251587)
van Heumen, W. R., Claxton, C. & Pickles, J. O. Expression of EphA4 in developing inner ears of the mouse and guinea pig. Hear. Res. 139, 42-50 (2000)
Pickles, J. O., Claxton, C. & Van Heumen, W. R. Complementary and layered expression of Ephs and ephrins in developing mouse inner ear. J. Comp. Neurol. 449, 207-216 (2002) (Pubitemid 34734280)
Dufour, A. et al. Area specificity and topography of thalamocortical projections are controlled by ephrin/Eph genes. Neuron 39, 453-465 (2003) (Pubitemid 36937047)
Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563-574 (2000)
Hafidi, A. Peripherin-like immunoreactivity in type II spiral ganglion cell body and projections. Brain Res. 805, 181-190 (1998) (Pubitemid 29005134)
Himanen, J. P. et al. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat. Neurosci. 7, 501-509 (2004)
Ehret, G. Behavioural studies on auditory development in mammals in relation to higher nervous system functioning. Acta Otolaryngol. Suppl. 421, 31-40 (1985) (Pubitemid 15058253)
Fuchs, P. A., Glowatzki, E. & Moser, T. The afferent synapse of cochlear hair cells. Curr. Opin. Neurobiol. 13, 452-458 (2003) (Pubitemid 37088236)
Matthews, G. & Fuchs, P. The diverse roles of ribbon synapses in sensory neurotransmission. Nat. Rev. Neurosci. 11, 812-822 (2010)
Schmitz, F., Königstorfer, A. & Südhof, T. C. RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function. Neuron 28, 857-872 (2000) (Pubitemid 32038077)
Liberman, M. C., Dodds, L. W. & Pierce, S. Afferent and efferent innervation of the cat cochlea: quantitative analysis with light and electron microscopy. J. Comp. Neurol. 301, 443-460 (1990) (Pubitemid 20368505)
Kujawa, S. G. & Liberman, M. C. Adding insult to injury: cochlear nerve degeneration after 'temporary' noise-induced hearing loss. J. Neurosci. 29, 14077-14085 (2009)
Gao, P. P. et al. Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5: implications in the development of thalamocortical projections. Proc. Natl Acad. Sci. USA 95, 5329-5334 (1998)
Brors, D. et al. EphA4 provides repulsive signals to developing cochlear ganglion neurites mediated through ephrin-B2 and-B3. J. Comp. Neurol. 462, 90-100 (2003) (Pubitemid 36700387)
Coate, T. M. et al. Otic mesenchyme cells regulate spiral ganglion axon fasciculation through a Pou3f4/EphA4 signaling pathway. Neuron 73, 49-63 (2012)
Grunwald, I. C. et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nat. Neurosci. 7, 33-40 (2004) (Pubitemid 38032165)
Ellis, C. et al. A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene 12, 1727-1736 (1996) (Pubitemid 26146297)
Wahl, S., Barth, H., Ciossek, T., Aktories, K. & Mueller, B. K. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J. Cell. Biol. 149, 263-270 (2000) (Pubitemid 30227145)
Yue, X., Dreyfus, C., Kong, T. A. & Zhou, R. A subset of signal transduction pathways is required for hippocampal growth cone collapse induced by ephrin-A5. Dev. Neurobiol. 68, 1269-1286 (2008)
Sahin, M. et al. Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46, 191-204 (2005) (Pubitemid 40545776)
Zhou, L. et al. EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association, and dendritic spine morphology. J. Neurosci. 27, 5127-5138 (2007) (Pubitemid 46741773)
Parri, M. et al. EphrinA1 activates a Src/focal adhesion kinase-mediated motility response leading to rho-dependent actino/myosin contractility. J. Biol. Chem. 282, 19619-19628 (2007) (Pubitemid 47100120)
Melcher, J. R. & Kiang, N. Y. Generators of the brainstem auditory evoked potential in cat. III: Identified cell populations. Hear. Res. 93, 52-71 (1996) (Pubitemid 26164851)
Charizopoulou, N. et al. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat. Commun. 2, 201 (2011)
Ernfors, P., Van De Water, T., Loring, J. & Jaenisch, R. Complementary roles of BDNF and NT-3 in vestibular and auditory development. Neuron 14, 1153-1164 (1995)
Fritzsch, B., Tessarollo, L., Coppola, E. & Reichardt, L. F. Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance. Prog. Brain. Res. 146, 265-278 (2004) (Pubitemid 37541388)
Echteler, S. M. Developmental segregation in the afferent projections to mammalian auditory hair cells. Proc. Natl Acad. Sci. USA 89, 6324-6327 (1992)
Simmons, D. D. A transient afferent innervation of outer hair cells in the postnatal cochlea. Neuroreport 5, 1309-1312 (1994) (Pubitemid 24219219)
Kao, T. J. & Kania, A. Ephrin-mediated cis-attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron 71, 76-91 (2011)
Carvalho, R. F. et al. Silencing of EphA3 through a cis interaction with ephrinA5. Nat. Neurosci. 9, 322-330 (2006) (Pubitemid 43290961)
Dudanova, I. & Klein, R. The axon's balancing act: cis-and trans-interactions between Ephs and ephrins. Neuron 71, 1-3 (2011)
Marquardt, T. et al. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 121, 127-139 (2005)
Koundakjian, E. J., Appler, J. L. & Goodrich, L. V. Auditory neurons make stereotyped wiring decisions before maturation of their targets. J. Neurosci. 27, 14078-14088 (2007) (Pubitemid 351377863)
Ruthazer, E. S. & Cline, H. T. Insights into activity-dependent map formation from the retinotectal system: a middle-of-the-brain perspective. J. Neurobiol. 59, 134-146 (2004) (Pubitemid 38391813)
Feldheim, D. A. et al. Loss-of-function analysis of EphA receptors in retinotectal mapping. J. Neurosci. 24, 2542-2550 (2004) (Pubitemid 38327967)
Triplett, J. W. et al. Competition is a driving force in topographic mapping. Proc. Natl Acad. Sci. USA 108, 19060-19065 (2011)
Miko, I. J., Henkemeyer, M. & Cramer, K. S. Auditory brainstem responses are impaired in EphA4 and ephrin-B2 deficient mice. Hear. Res. 235, 39-46 (2008) (Pubitemid 350297666)
Knipper, M. et al. Transient expression of NMDA receptors during rearrangement of AMPA-receptor expressing fibers in the developing inner ear. Cell Tissue Res. 287, 23-41 (1997) (Pubitemid 27029630)
Beurg, M. et al. Calcium-and otoferlin dependent exocytosis by immature outer hair cells. J. Neurosci. 28, 1798-1803 (2008) (Pubitemid 351302659)
Knirsch, M. et al. Persistence of Ca(v)1. 3 Ca2 channels in mature outer hair cells supports outer hair cell afferent signaling. J. Neurosci. 27, 6442-6451 (2007) (Pubitemid 46920367)
Lallemend, F. et al. New insights into peripherin expression in cochlear neurons. Neuroscience 150, 212-222 (2007) (Pubitemid 350198694)
Hasson, T., Heintzelman, M. B., Santos-Sacchi, J., Corey, D. P. & Mooseker, M. S. Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc. Natl Acad. Sci. USA 92, 9815-9819 (1995)
Yang, D., Thalmann, I., Thalmann, R. & Simmons, D. D. Expression of alpha and beta parvalbumin is differentially regulated in the rat organ of corti during development. J. Neurobiol. 58, 479-492 (2004) (Pubitemid 38263947)
Richter, C. P., Kumar, G., Webster, E., Banas, S. K. & Whitlon, D. S. Unbiased counting of neurons in the cochlea of developing gerbils. Hear. Res. 278, 43-51 (2011)
Flenniken, A. M., Gale, N. W., Yancopoulos, G. D. & Wilkinson, D. G. Distinct and overlapping expression patterns of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis. Dev. Biol. 179, 382-401 (1996) (Pubitemid 26384083)
Nieto, M. A., Gilardi-Hebenstreit, P., Charnay, P. & Wilkinson, D. G. A receptor protein tyrosine kinase implicated in the segmental patterning of the hindbrain and mesoderm. Development 116, 1137-1150 (1992) (Pubitemid 23042453)
Tiveron, M. C., Hirsch, M. R. & Brunet, J. F. The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system. J. Neurosci. 16, 7649-7660 (1996)
Knöll, B., Weinl, C., Nordheim, A. & Bonhoeffer, F. Stripe assay to examine axonal guidance and cell migration. Nat. Protoc. 2, 1216-1224 (2007) (Pubitemid 46901301)
Buran, B. N. et al. Onset coding is degraded in auditory nerve fibres from mutant mice lacking synaptic ribbons. J. Neurosci. 30, 7587-7597 (2010).
