title: EphA7 regulates spiral ganglion innervation of cochlear hair cells.
abstract: During the development of periphery auditory circuitry, spiral ganglion neurons (SGNs) form a spatially precise pattern of innervation of cochlear hair cells (HCs), which is an essential structural foundation for central auditory processing. However, molecular mechanisms underlying the developmental formation of this precise innervation pattern remain not well understood. Here, we specifically examined the involvement of Eph family members in cochlear development. By performing RNA-sequencing for different types of cochlear cell, in situ hybridization, and immunohistochemistry, we found that EphA7 was strongly expressed in a large subset of SGNs. In EphA7 deletion mice, there was a reduction in the number of inner radial bundles originating from SGNs and projecting to HCs as well as in the number of ribbon synapses on inner hair cells (IHCs), as compared with wild-type or heterozygous mutant mice, attributable to fewer type I afferent fibers. The overall activity of the auditory nerve in EphA7 deletion mice was also reduced, although there was no significant change in the hearing intensity threshold. In vitro analysis further suggested that the reduced innervation of HCs by SGNs could be attributed to a role of EphA7 in regulating outgrowth of SGN neurites as knocking down EphA7 in SGNs resulted in diminished SGN fibers. In addition, suppressing the activity of ERK1/2, a potential downstream target of EphA7 signaling, either with specific inhibitors in cultured explants or by knocking out Prkg1, also resulted in reduced SGN fibers. Together, our results suggest that EphA7 plays an important role in the developmental formation of cochlear innervation pattern through controlling SGN fiber ontogeny. Such regulation may contribute to the salience level of auditory signals presented to the central auditory system.
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Neuroscience Graduate Program, University Of Southern California, Los Angeles, California.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Neuroscience Graduate Program, University Of Southern California, Los Angeles, California.
authors.forename: Leena A
authors.initials: LA
authors.lastname: Ibrahim
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.
authors.forename: Sheng-Zhi
authors.initials: SZ
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology of Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Department of Psychiatry, Keck School Of Medicine, University Of Southern California, Los Angeles, California.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgrafov
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Department of Psychiatry, Keck School Of Medicine, University Of Southern California, Los Angeles, California.
authors.forename: James A
authors.initials: JA
authors.lastname: Knowles
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Department of Psychiatry, Keck School Of Medicine, University Of Southern California, Los Angeles, California.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Department of Cell And Neurobiology, Keck School Of Medicine, University Of Southern California, Los Angeles, California.
authors.forename: Huizhong W
authors.initials: HW
authors.lastname: Tao
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University Of Southern California, Los Angeles, California, 90033.|Department of Physiology and Biophysics, Keck School Of Medicine, University Of Southern California, Los Angeles, California.
authors.forename: Li I
authors.initials: LI
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D003051:Cochlea / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020935:MAP Kinase Signaling System / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D036141:Receptor, EphA7 / Q000235:genetics / Q000378:metabolism*; D013136:Spiral Ganglion / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D036141:Receptor, EphA7; C581330:epha7 receptor, mouse; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569720:Prkg1 protein, mouse
keywords: axon guidance molecule; cochlear development; hair cell; peripheral auditory system; spiral ganglion