Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea.
Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea.
复制标题
Wnt 激活可防止新霉素诱导的小鼠耳蜗毛细胞损伤
DOI：
10.1038/cddis.2016.35
复制
发表时间：
2016-03-10
影响因子：
9
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Liu L;Chen Y;Qi J;Zhang Y;He Y;Ni W;Li W;Zhang S;Sun S;Taketo MM;Wang L;Chai R;Li H
最近的研究报道了Wnt/β-catenin信号在小鼠耳蜗毛细胞（HC）发育、再生和分化中的作用；然而，Wnt/β-catenin信号在HC保护中的作用尚不清楚。在这项研究中，我们利用转基因小鼠特异性敲除或过度激活hcc中典型的Wnt信号介质β-catenin，这使我们能够研究Wnt/β-catenin信号在保护hcc免受新霉素诱导损伤中的作用。我们首先表明，HC中β-catenin的丢失使它们更容易受到新霉素诱导的损伤，而HC中β-catenin的组成性激活在体内和体外都减少了HC的丢失。我们随后发现，β-catenin在hcc中的缺失增加了新霉素损伤引起的caspase介导的细胞凋亡，而β-catenin过表达抑制caspase介导的细胞凋亡。最后，我们证明了β-catenin在hcc中的缺失导致叉头盒O3转录因子（Foxo3）和Bim的表达增加，同时抗氧化酶的表达降低；因此，新霉素治疗后活性氧（ROS）水平升高，这可能是hcc氨基糖苷敏感性升高的原因。相反，β-catenin过表达降低了Foxo3和Bim的表达以及ROS水平，表明β-catenin对新霉素诱导的HC损失具有保护作用。我们的研究结果表明，Wnt/β-catenin信号在保护HC免受新霉素诱导的HC损失中具有重要作用，因此可能成为预防HC死亡的新治疗靶点。
Recent studies have reported the role of Wnt/β-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/β-catenin signaling in HC protection remains unknown. In this study, we took advantage of transgenic mice to specifically knockout or overactivate the canonical Wnt signaling mediator β-catenin in HCs, which allowed us to investigate the role of Wnt/β-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of β-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of β-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of β-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while β-catenin overexpression inhibited caspase-mediated apoptosis. Finally, we demonstrated that loss of β-catenin in HCs led to increased expression of forkhead box O3 transcription factor (Foxo3) and Bim along with decreased expression of antioxidant enzymes; thus, there were increased levels of reactive oxygen species (ROS) after neomycin treatment that might be responsible for the increased aminoglycoside sensitivity of HCs. In contrast, β-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that β-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/β-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss and thus might be a new therapeutic target for the prevention of HC death.