FGF22 promotes generation of ribbon synapses through downregulating MEF2D
FGF22 promotes generation of ribbon synapses through downregulating MEF2D
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FGF22 通过下调 MEF2D 促进带状突触的生成
DOI：
10.18632/aging.103042
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发表时间：
2020-04-15
期刊：
影响因子：
5.2
通讯作者：
Yang, Jun
中科院分区：
文献类型：
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作者：
Li, Shuna;He, Jingchun;Yang, Jun
耳蜗带状突触在内毛细胞（inner hair cells，IHC）向螺旋神经节神经元快速、精确的声信号传递中起着关键作用，而噪声和老化可损伤带状突触，导致感音神经性听力损失。最近，我们描述了减少成纤维细胞生长因子22（FGF22）和增强肌细胞增强因子2D（MEF2D）在耳毒性小鼠模型受损的带状突触。在这里，我们研究了FGF22/MEF2D调节的带状突触损伤的机制。我们产生了携带FGF 22、shFGF 22、MEF 2D、shMEF 2D、钙调磷酸酶（CalN）、shCalN或相应的乱序对照的腺相关病毒（AAV），用于转导培养的小鼠毛细胞。我们发现FGF22是MEF2D的抑制因子，但不是相反。此外，FGF22可能诱导钙流入IHC中以激活CalN，随后抑制MEF2D。AAV-shFGF22的共输注激活MEF2D，减少带状突触数量和受损的听力功能，这些都被AAV-shMEF2D的共输注所消除。因此，我们的数据表明，带状突触可能受到FGF 22/钙/CalN/MEF2D信号转导的调节，这意味着新的听力损失治疗靶点。
Cochlear ribbon synapses play a pivotal role in the prompt and precise acoustic signal transmission from inner hair cells (IHCs) to the spiral ganglion neurons, while noise and aging can damage ribbon synapses, resulting in sensorineural hearing loss. Recently, we described reduced fibroblast growth factor 22 (FGF22) and augmented myocyte enhancer factor 2D (MEF2D) in an ototoxicity mouse model with impaired ribbon synapses. Here, we investigated the mechanisms that underlie the FGF22/MEF2D- regulated impairment of ribbon synapses. We generated adeno-associated virus (AAV) carrying FGF22, shFGF22, MEF2D, shMEF2D, calcineurin (CalN), shCalN or corresponding scramble controls for transduction of cultured mouse hair cells. We found that FGF22 was a suppressor for MEF2D, but not vice versa. Moreover, FGF22 likely induced increases in the calcium influx into IHCs to activate CalN, which subsequently inhibited MEF2D. Cochlear infusion of AAV-shFGF22 activated MEF2D, reduced ribbon synapse number and impaired hearing function, which were all abolished by co-infusion of AAV-shMEF2D. Hence, our data suggest that the ribbon synapses may be regulated by FGF22/calcium/CalN/MEF2D signaling, which implied novel therapeutic targets for hearing loss.