Notch Signaling in Ear Development

描述(申请人提供)：哺乳动物的内耳是一个精致复杂的器官，由充满液体的管道系统组成，中间有高度花纹的感觉区域，是听力和平衡所必需的。不幸的是，当受到损伤时，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，这使得了解它们的发育成为设计未来疗法的重要先决条件。这项提议试图测试一个假定的感觉基因，Notch配体锯齿状1(Jag1)的作用。Notch信号此前已被证明对毛细胞和支持细胞分化具有重要作用，它介导了侧向抑制。然而，从以前的研究中可以清楚地看出，Jag1不太可能在侧向抑制中发挥主要作用。这一提议将检验Jag1转而参与耳朵感觉器官规范的假设。了解Jag1在耳朵发育中的作用的一个主要障碍是，该基因缺失的小鼠在胚胎发育过程中过早死亡。为了绕过这个问题，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近交系小鼠中存在修饰基因(S)，可导致Jag1+小鼠耳部缺陷。识别与Jag1相互作用的基因将进一步阐明这种Notch配体在耳朵发育中所起的作用，并有可能识别与耳朵的感觉规范有关的新基因。我们建议映射并最终克隆这些修改器(S)。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，为最终纠正环境或遗传对这些区域的侮辱提供基础。

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.