Notch Signaling during Organ of Corti Maturation and Maintenance

大多数耳聋和前庭疾病是由于体内关键细胞的丢失或功能障碍造成的 耳朵，包括毛细胞、支持细胞和神经元。一旦丢失或受损，这些细胞类型显示很少或没有 在哺乳动物内耳中再生的能力。近年来，取得了一些令人振奋的成果。 关于在内源性上皮中产生新毛细胞的方法，通常是通过转化 现有的支持细胞。Notch信号通路是调节细胞周期的关键途径。 毛细胞或支持细胞命运的决定，通过一个称为侧向抑制的过程。在这个系统中， 表达Notch配体的细胞激活周围细胞中的Notch，阻止他们收养头发 细胞的命运。这种信号产生了感觉马赛克，其中每个毛细胞被支持细胞包围。 抑制Notch可促进支持细胞转化为毛细胞，为 替换丢失的或功能失调的毛细胞。然而，Notch信号是一条经常发挥作用的强大途径 在开发过程中扮演多种角色。我们的初步结果表明，除了细胞命运的选择，Notch 也通过JAG1配体在耳蜗成熟或维持过程中发挥重要作用。具体地说，我们的 结果表明，JAG1缺失不会导致细胞命运改变，而是会导致听力障碍 类似于人类的听神经病。我们假设通过JAG1配体激活Notch是 耳蜗感觉觉成熟和/或维持所必需的。这里概述的建议 旨在验证这一假说，通过(1)建立Jag1基因在耳蜗上皮细胞中缺失的影响，(2) 确定介导JAG1效应的细胞类型和受体，以及(3)建立直接和间接靶点 用于JAG1-Notch1信令。了解Notch信号在出生后成熟和感觉中的作用 维护对于未来依赖于操纵毛细胞Notch信号的再生疗法是必不可少的 替补。 。

The majority of deafness and vestibular disorders occur due to loss or dysfunction of critical cells in the inner ear, including hair cells, supporting cells and neurons. Once lost or impaired, these cell types show little or no ability to regenerate in the mammalian inner ear. In recent years, there have been a number of exciting results regarding approaches to generate new hair cells in the endogenous epithelium, often through transformation of existing supporting cells. The Notch signaling pathway has been shown to be a key pathway in regulating the determination of the hair cell or supporting cell fate, through a process called lateral inhibition. In this system, cells expressing the Notch ligand activate Notch in the surrounding cells and prevent them from adopting a hair cell fate. This signaling creates the sensory mosaic in which each hair cell is surrounded by supporting cells. Inhibition of Notch can promote the conversion of supporting cells into hair cells, providing an avenue for replacing lost or dysfunctional hair cells. However, Notch signaling is a powerful pathway that often plays multiple roles during development. Our preliminary results indicate that in addition to cell fate choices, Notch also plays an essential role in cochlear maturation or maintenance via the JAG1 ligand. Specifically, our results demonstrate that JAG1 deletion does not cause cell fate alterations but instead leads to hearing deficits resembling auditory neuropathy in humans. We hypothesize that activation of Notch via the JAG1 ligand is required for aspects of sensory maturation and/or maintenance in the cochlea. The proposal outlined here aims to test this hypothesis, by (1) establishing the effects of deletion of Jag1 in the cochlear epithelium, (2) identifying the cell type and receptors that mediate JAG1 effects, and (3) establishing direct and indirect targets for JAG1-Notch1 signaling. Understanding the role of Notch signaling in postnatal maturation and sensory maintenance is essential for future regenerative therapies that rely on manipulating Notch signaling for hair cell replacement. .