UCL Ear Institute, 332 Gray's Inn Road, London WC1X 8EE, UK.
J Cell Sci. 2011 Apr 1;124(Pt 7):1145-55. doi: 10.1242/jcs.076141.
The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival. We performed a subtractive hybridisation screen in an inner-ear-derived cell line to find genes with differential expression in response to changes in Pou4f3 levels. The screen identified the stress-granule-associated protein Caprin-1 as being downregulated by Pou4f3. We demonstrated that this regulation occurs through the direct interaction of Pou4f3 with binding sites in the Caprin-1 5' flanking sequence, and describe the expression pattern of Caprin-1 mRNA and protein in the cochlea. Moreover, we found Caprin-1-containing stress granules are induced in cochlear hair cells following aminoglycoside-induced damage. This is the first report of stress granule formation in mammalian hair cells and suggests that the formation of Caprin-1-containing stress granules is a key damage response to a clinically relevant ototoxic agent. Our results have implications for the understanding of aminoglycoside-induced hearing loss and provide further evidence that stress granule formation is a fundamental cellular stress response.
POU4 转录因子家族对于不同感觉系统中特定细胞类型的存活是必需的。 Pou4f3 对于听觉感觉毛细胞的存活是必需的，人类 POU4F3 的几个突变导致听力损失。因此，Pou4f3 调节的基因可能对于毛细胞的存活至关重要。我们在内耳衍生细胞系中进行了差减杂交筛选，以寻找对 Pou4f3 水平变化有差异表达的基因。该筛选鉴定出应激颗粒相关蛋白 Caprin-1 是受 Pou4f3 下调的。我们证明这种调节是通过 Pou4f3 与 Caprin-1 5'侧翼序列上的结合位点的直接相互作用发生的，并描述了 Caprin-1 mRNA 和蛋白在耳蜗中的表达模式。此外，我们发现氨基糖苷类诱导损伤后，Caprin-1 包含的应激颗粒在耳蜗毛细胞中诱导形成。这是哺乳动物毛细胞中应激颗粒形成的第一个报道，表明 Caprin-1 包含的应激颗粒的形成是对临床相关耳毒性药物的关键损伤反应。我们的结果对于理解氨基糖苷类诱导的听力损失具有重要意义，并进一步证明应激颗粒的形成是一种基本的细胞应激反应。
