Notch Signaling in Ear Development

耳朵发育中的Notch信号

• 批准号: 6584457
• 负责人: Amy Kiernan
• 金额: $ 4.81万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584457
• 关键词: biological signal transduction; developmental genetics; ear hair cell; gene expression; gene interaction; gene targeting; genetic mapping; genetically modified animals; genome; genotype; histogenesis; immunocytochemistry; laboratory mouse; labyrinth; membrane proteins; molecular cloning; morphology; nucleic acid sequence; phenotype; postdoctoral investigator; quantitative trait loci; receptor; scanning electron microscopy

DESCRIPTION (provided by applicant): The mammalian inner ear is an exquisitely complex organ composed of a fluid-filled duct system punctuated by highly patterned sensory regions necessary for hearing and balance. Unfortunately, when damaged, the mammalian ear demonstrates little or no ability to regenerate these regions, making understanding their development an important prerequisite for the design of future therapies. This proposal seeks to test the role of one putative sensory gene, the Notch ligand Jagged 1 (Jag1). Notch signaling has previously been demonstrated to be important for hair cell and supporting cell differentiation by mediating lateral inhibition. However, it is clear from previous studies that Jag1 is unlikely to play a major role in lateral inhibition. This proposal will test the hypothesis that Jag1 is instead involved in sensory organ specification in the ear. A major impediment to understanding the role of Jag1 in ear development is that mice deleted for this gene die early during embryogenesis. In order to circumvent this problem, a conditional loss-of-function allele will be created using the Cre/loxP system. Preliminary data shows that there are modifier(s) in the C3H inbred mouse strain that cause ear defects in Jag1 + mice. Identifying genes that interact with Jag1 will further elucidate the role that this Notch ligand plays in ear development and potentially identify new genes involved in sensory specification in the ear. We propose to map and eventually clone these modifier(s). Data collected from these experiments will further our understanding of sensory field specification in the mammalian inner ear, providing a basis for eventually correcting environmental or genetic insults to these regions.

描述（由申请人提供）：哺乳动物的内耳是一个精美的复杂器官，由充满流体的管道系统组成，该系统由听力和平衡所必需的高度图案的感觉区域打断。不幸的是，当损坏时，哺乳动物的耳朵几乎没有或根本没有再生这些区域的能力，使他们的发展成为设计未来疗法的重要前提。该建议旨在测试一个假定的感觉基因的作用，即Notch配体锯齿状1（JAG1）。先前已证明Notch信号传导对于毛细胞和通过介导横向抑制作用支持细胞分化很重要。但是，从以前的研究中可以明显看出，JAG1不太可能在横向抑制中起主要作用。该提案将检验以下假设：JAG1相反地参与了耳朵中的感觉器官规范。理解JAG1在耳朵发育中的作用的主要障碍是，在胚胎发生过程中为该基因删除了该基因的小鼠。为了避免此问题，将使用CRE/LOXP系统创建有条件的功能丧失等位基因。初步数据表明，在C3H近交小鼠菌株中有修饰符在JAG1 +小鼠中导致耳朵缺陷。识别与JAG1相互作用的基因将进一步阐明该缺口配体在耳朵发育中起的作用，并有可能识别与耳朵中感觉规范有关的新基因。我们建议映射并最终克隆这些修饰符。从这些实验中收集的数据将进一步了解我们对哺乳动物内耳中感觉场规范的理解，从而为最终纠正对这些区域的环境或遗传侮辱提供了基础。