Molecular Basis Of Transduction In Auditory Sensory Orga

听力和平衡依赖于感觉毛细胞，这些毛细胞配备了机械敏感的微绒毛样细胞器，称为立体纤毛，能够通过位于其尖端的机械门控通道检测纳米尺度上的位移。哺乳动物的听觉毛细胞是终末分化的，不能再生。虽然它们的立体纤毛对机械振动非常敏感，结构有序，容易因过度刺激而损坏，但它们一生都能保持良好的工作状态。每根立体纤毛由几百根平行的、均匀极化的、有规则交联的肌动蛋白丝组成的刚性准晶阵列支撑。肌动蛋白丝的定向使正极（倒钩）端在立纤毛的尖端，负极（尖）端在基部。这种肌动蛋白的组织结构与微绒毛和丝状足中的肌动蛋白结构有许多相同的结构原理，但可达120？长度为M。这种有序的肌动蛋白结构是如何构建、调节和更新的，这在很大程度上是未知的。我们现在已经证明，毛细胞感觉立体纤毛核心的看似静态的肌动蛋白副晶体，通过在立体纤毛尖端自我复制，向后移动，并在基部自我拆除，从而经历了不断的更新。跑步是肌动蛋白丝的一种动态行为，在各种形式的细胞运动中起着至关重要的作用。然而，人们对这一过程在非运动肌动蛋白组装体中的发生和调控知之甚少。研究表明，跑步机速率与立体纤毛的长度成比例，并受到局部物理参数的调节，如包覆膜和立体纤毛连接上的张力，以及位于尖端和肌动蛋白旁晶的肌凝蛋白。我们认为，这种受调节的跑步动态塑造了立体纤毛的功能结构，并在过度刺激后的恢复中发挥了核心作用。这种准晶肌动蛋白集合的动态视图突出了组织良好的细胞结构如何在进行连续自我更新的同时保持稳态结构、自我调节和修复。

Hearing and balance depend on sensory hair cells equipped with mechanosensitive, microvilli-like organelles, called stereocilia, that are capable of detecting displacements on a nanometer scale through mechanically gated channels located at their tips. Mammalian auditory hair cells are terminally differentiated and do not regenerate. While their stereocilia are exquisitely sensitive to mechanical vibration, orderly structured, and easily damaged by over-stimulation, they are maintained in proper working order for a lifetime. Each stereocilium is supported by a rigid paracrystalline array of several hundred parallel, uniformly polarized and regularly cross-linked actin filaments. The actin filaments are oriented such that the plus (barbed) ends are at the tips of the stereocilia and the minus (pointed) ends at the base. This organization of actin shares many construction principles with the actin formations in microvilli and filopodia yet can be up to 120?m in length. How such ordered actin formations are built, regulated, and renewed is largely unknown. We have now demonstrated that the seemingly static actin paracrystal at the core of sensory stereocilia of hair cells, undergoes continuous renewal enabled by reproducing itself at the stereocilia tips, treadmilling rearwards, and dismantling itself at the base. Treadmilling is a dynamic behavior of actin filaments that plays a crucial role in various forms of cell motility. However, little is known about the occurrence and regulation of this process in non-motile actin assemblies. We show that treadmill rates are scaled to the length of stereocilia and are modulated by local physical parameters, such as tension on the encapsulating membrane and on stereocilia links, as well as by myosins located at the tips and alongside the actin paracrystal. We propose that this regulated treadmilling dynamically shapes the functional architecture of stereocilia and plays a central role in recovery from over-stimulation. Such a dynamic view of a paracrystalline actin ensemble highlights how well organized cellular structures can maintain steady state structure, self-adjustment, and repair while undergoing continuous self-renewal.