Institute for Science and Technology in Medicine, Keele University, Keele ST5 5BG, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13898-903. doi: 10.1073/pnas.1304644110. Epub 2013 Aug 5.
Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 null-mutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss.
哺乳动物听觉系统中的机械转导依赖于从感觉毛细胞的顶表面突出的毛束中的机械敏感通道。每个束中的单个静纤毛包含一个紧密排列的肌动蛋白丝核心，其长度在发育过程中和成年期动态调节。我们表明，表皮生长因子受体途径底物 8（Eps8）L2 是一种新鉴定的毛束蛋白，它是 Eps8 样蛋白家族的成员，定位于耳蜗和前庭毛细胞的静纤毛的尖端。它具有时空表达模式，与 Eps8 互补。在耳蜗中，尽管 Eps8 对于静纤毛的初始伸长是必需的，但 Eps8L2 对于成年毛细胞中它们的维持是必需的。在这两种蛋白都缺失的情况下，耳蜗毛束的有序阶梯结构会退化。与缺乏 Eps8 相关的早期严重听力损失相反，Eps8L2 缺失突变小鼠表现出迟发性、进行性听力损失，这与毛束形态的逐渐恶化直接相关。我们得出结论，Eps8L2 是维持听觉毛束的阶梯结构和机械感觉功能所必需的。它补充了 Eps8 的发育作用，是进行性年龄相关性听力损失的候选基因。
