cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway
cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway
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DOI：
10.1007/s10162-009-0205-8
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发表时间：
2010-06-01
影响因子：
2.4
通讯作者：
Oberholtzer, John Carl
中科院分区：
文献类型：
--
作者：
Bell, Thomas J.;Oberholtzer, John Carl
感音神经性听力缺陷是由于听觉毛细胞的丧失造成的。这种听力损失对于人类和哺乳动物来说是永久性的，因为毛细胞不会自发更换。对于鸟类等其他动物来说，情况并非如此。鸟类耳蜗的损伤会引起支持细胞的增殖和具有功能的替代毛细胞的产生。信号转导途径在临床上可作为潜在的治疗靶点，因此人们对识别调节替代毛细胞形成的关键信号转导途径非常感兴趣。在我们实验室之前的一项研究中，我们表明，在没有声音或氨基糖苷类治疗的情况下，毛喉素 (FSK) 治疗可诱导听觉支持细胞增殖和替代毛细胞的形成。在这里，我们发现 FSK 诱导的支持细胞增殖是由鸟类支持细胞中环磷酸腺苷 (cAMP) 的细胞特异性积累和细胞外信号调节激酶 (ERK) 丝裂原激活蛋白激酶 (MAPK) 途径介导的。通过免疫染色和药理学分析相结合，我们发现 FSK 治疗可增加禽类听觉支持细胞中的 cAMP 水平，并且几种 ERK MAP 抑制剂可有效阻止 FSK 诱导的支持细胞增殖。接下来，我们通过蛋白质印迹和免疫染色分析了禽类听觉上皮细胞中几种 ERK MAPK 信号分子的表达以及禽类听觉支持细胞中 B-Raf 的细胞特异性表达。总的来说，这些数据表明，FSK 诱导的禽类听觉上皮细胞增殖是由支持细胞中 cAMP 水平的增加和支持细胞中 ERK MAPK 家族成员 B-Raf 的细胞特异性表达介导的。
Sensorineural hearing deficiencies result from the loss of auditory hair cells. This hearing loss is permanent in humans and mammals because hair cells are not spontaneously replaced. In other animals such as birds, this is not the case. Damage to the avian cochlea evokes proliferation of supporting cells and the generation of functionally competent replacement hair cells. Signal transduction pathways are clinically useful as potential therapeutic targets, so there is significant interest in identifying the key signal transduction pathways that regulate the formation of replacement hair cells. In a previous study from our lab, we showed that forskolin (FSK) treatment induces auditory supporting cell proliferation and formation of replacement hair cells in the absence of sound or aminoglycoside treatment. Here, we show that FSK-induced supporting cell proliferation is mediated by cell-specific accumulation of cyclic adenosine monophosphate (cAMP) in avian supporting cells and the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. By a combination of immunostaining and pharmacological analyses, we show that FSK treatment increases cAMP levels in avian auditory supporting cells and that several ERK MAP inhibitors effectively block FSK-induced supporting cell proliferation. Next, we demonstrate by Western blotting and immunostaining analyses the expression of several ERK MAPK signaling molecules in the avian auditory epithelium and the cell-specific expression of B-Raf in avian auditory supporting cells. Collectively, these data suggest that FSK-induced supporting cell proliferation in the avian auditory epithelium is mediated by increases of cAMP levels in supporting cells and the cell-specific expression of the ERK MAPK family member B-Raf in supporting cells.