Notch Signaling in Ear Development

描述（由申请人提供）：哺乳动物内耳是一个非常复杂的器官，由充满液体的管道系统组成，由听力和平衡所必需的高度模式的感觉区域组成。不幸的是，当受损时，哺乳动物的耳朵表现出很少或没有再生这些区域的能力，这使得了解它们的发展成为设计未来治疗方法的重要先决条件。这项提议旨在测试一个假定的感觉基因，缺口配体Jagged 1 （Jag1）的作用。Notch信号在毛细胞和支持细胞分化中起着重要的作用。然而，从先前的研究中可以清楚地看出，Jag1不太可能在侧抑制中起主要作用。这一提议将验证Jag1参与耳朵感觉器官规范的假设。理解Jag1在耳朵发育中的作用的一个主要障碍是，缺失该基因的小鼠在胚胎发生过程中死亡早。为了避免这个问题，将使用Cre/loxP系统创建一个条件功能丧失等位基因。初步数据显示，C3H自交系小鼠中存在引起Jag1 +小鼠耳部缺陷的修饰因子。鉴定与Jag1相互作用的基因将进一步阐明Notch配体在耳朵发育中的作用，并有可能鉴定出与耳朵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加深我们对哺乳动物内耳感觉场规范的理解，为最终纠正这些区域的环境或遗传损害提供基础。

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.