Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function.
Ephrins and Ephs in cochlear innervation and implications for advancing cochlear implant function.
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Ephrins 和 Ephs 在耳蜗神经支配中的作用及其对促进人工耳蜗功能的影响。
DOI：
10.1002/lary.25066
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Henkemeyer,MarkJ
中科院分区：
文献类型：
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作者：
Lee,KennethH;Warchol,MarkE;Pawlowski,KarenS;Shao,Dongmei;Koulich,Elena;Zhou,ConstanceQ;Lee,James;Henkemeyer,MarkJ
目的/假设确定在内耳中由Eph/ephrin相互作用引起的神经元寻路线索是否在建立耳蜗的音调定位神经支配中起作用。研究设计在小鼠和小鸡的内耳中评价Eph和ephrin的蛋白质表达。随后，在体外，在体内，和功能性电生理研究表明，Ephs和ephrin发挥调节正常的神经支配模式在小鼠innerear.MethodsEph和ephrin蛋白表达的作用，确定在内耳免疫印迹和本地化荧光免疫组织化学和X-gal染色。通过与表达EphB 2的COS-1细胞共培养来评估Eph/ephrin对神经突生长的影响。用亲脂性染料示踪法和听性脑干反应（ABR）法研究了干扰Eph/ephrin信号通路对耳蜗神经支配的解剖学影响，并观察了干扰Eph/ephrin信号通路对耳蜗神经支配的功能影响。庆大霉素耳毒性后ephrin-A2免疫反应性的变化与鸡耳蜗毛细胞损失和再生的时空模式一致。EphB 2抑制螺旋神经节细胞突起的生长。EphB 1、EphB 2和EphB 3基因敲除小鼠的内耳神经支配异常，ABR阈值升高，提示听力损失。ConclusionsEphrin-A2可能参与鸡的神经节细胞向毛细胞的引导。Eph/ephrin信号传导的中断导致异常神经支配和听力损失，表明这些蛋白质在小鼠耳蜗中建立正常神经支配模式中起作用。
Objectives/HypothesisDetermine if the neuronal pathfinding cues resulting from Eph/ephrin interaction in the inner ear play a role in establishing the tonotopic innervation of the cochlea.Study DesignProtein expression of Ephs and ephrins was evaluated in the inner ear of mice and chicks. Subsequently,in vitro,in vivo, and functional electrophysiologic studies were performed to indicate that Ephs and ephrins play a role regulating the normal innervation patterns in the mouse inner ear.MethodsEph and ephrin protein expression was identified in the inner ear by western blotting and localized by fluorescence immunohistochemistry and X‐gal staining. Eph/ephrin effects on neurite outgrowth was assessed via co‐culture with EphB2 expressing COS‐1 cells. Anatomic effects of disrupting Eph/ephrin signaling on cochlear innervation were determined with lipophilic dye tracing and functional effects with auditory brainstem response (ABR).ResultsExpression of several different Ephs and ephrins were found in the inner ear of chicks and mice. The changes in ephrin‐A2 immunoreactivity after gentamicin ototoxicity coincide with the spatio‐temporal pattern of hair cell loss and regeneration in the chick cochlea. EphB2 inhibited outgrowth of spiral ganglion cell neurites. Knockout mice with null function of EphB1, EphB2, and EphB3 demonstrated abnormal inner ear innervation and elevated ABR thresholds, indicating hearing loss.ConclusionsEphrin‐A2 may be involved in the guidance of ganglion cells to hair cells in the chick. Disruption of Eph/ephrin signaling results in abnormal innervation and hearing loss, suggesting that these proteins play a role in establishing normal innervation patterns in the mouse cochlea.Level of EvidenceNALaryngoscope, 125:1189–1197, 2014