Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts 02115, Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
J Neurosci. 2013 Sep 18;33(38):15086-94. doi: 10.1523/JNEUROSCI.1489-13.2013.
Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.
Isl1 是 LIM 同源结构域转录因子，在多种组织的发育和分化中起着关键作用。在小鼠内耳中，Isl1 在内耳囊中前感觉区、年轻的毛细胞和支持细胞中表达，而在出生后的听觉毛细胞中不再表达。为了评估出生后毛细胞中持续的 Isl1 表达如何影响毛细胞发育和耳蜗功能，我们创建了一种转基因小鼠模型，其中 Pou4f3 启动子特异性地在毛细胞中驱动 Isl1 过表达。Isl1 过表达的毛细胞发育正常，形态和耳蜗功能（听觉脑干反应和耳声发射）均可见。当小鼠长到 17 个月时，野生型（WT）对照显示出与背景品系（C57BL/6J）中年龄相关性听力损失（ARHL）特征性的进行性阈值升高和外毛细胞损失。相比之下，Isl1 转基因小鼠的阈值升高明显较少，毛细胞存活。此外，Isl1 过表达可保护耳朵免受噪声性听力损失（NIHL）的影响：与 WT 同窝仔相比，ABR 阈值变化和毛细胞死亡均显著减少。我们的模型提示 ARHL 和 NIHL 具有共同的机制，并提供了证据表明毛细胞特异性 Isl1 表达可以促进毛细胞存活，从而最大程度地减少正常衰老和/或声过度暴露引起的听力障碍。
