Lrig interactions with ErbB pathways in the inner ear

描述(申请人提供)：听觉和平衡感起源于复杂的内耳迷宫。检测声音需要正确的耳蜗结构，而平衡需要正确的前庭器官的结构和方向。对促进内耳形态发生的基因的了解将有助于深入了解许多人类听力和平衡障碍的根本原因。我们已经确定了Ig超家族的一个新成员，Lrig3，它是前庭系统正常形成所必需的。Lrig3突变小鼠的外侧半规管(SCC)被截断，因此表现出旋转行为。对这些突变体的详细分析将有助于揭示Lrig3在导管形成中的功能，并可能揭示其他功能，因为所有三个Lrig基因都以重叠的模式在内耳和大脑中表达。一个家族成员，Lrig1，结合并调节ErbB受体家族的降解，增加了Lrig3也通过Erb途径发挥作用的可能性。这一假说将通过表达研究和体外生化分析来验证。这些研究将阐明复杂组织形态发生的细胞机制，并可能揭示这一新的细胞表面分子家族的分子功能。了解Lrig3突变在鳞状细胞癌形态发生中的细胞和分子后果不仅将突出这些分子在内耳发育中的作用，而且还将使我们深入了解侧管的发育，因为它与更知名的前、后管发育相比较。虽然Lrig3突变体的外侧半规管被截断，但包括外侧壶腹在内的前、后导管仍未受到影响。这种缺陷的特异性使Lrig3成为一个特别有趣的研究蛋白质，因为侧管是许多前庭疾病中最常见的结构，例如在Charge综合征患者中观察到的结构。

DESCRIPTION (provided by applicant): The perceptions of hearing and balance originate within the complex labyrinths of the inner ear. Correct formation of the cochlea is required for the detection of sound, while correct formation and orientation of the vestibular organs is required for balance. Knowledge of the genes that promote inner ear morphogenesis will provide insights into the root causes of many human hearing and balance disorders. We have identified a novel member of the Ig superfamily, Lrig3, that is required for proper formation of the vestibular system. Lrig3 mutant mice have a truncated lateral semicircular canal (SCC) and therefore exhibit circling behavior. A detailed analysis of these mutants will shed light on the function of Lrig3 in canal formation and may reveal additional functions, as all three Lrig genes are expressed in overlapping patterns in the inner ear and in the brain. One family member, Lrig1, binds to and regulates degradation of the ErbB family of receptors, raising the possibility that Lrig3 also acts through the Erb pathway. This hypothesis will be tested with expression studies and in vitro biochemical assays. These studies will elucidate the cellular mechanisms of complex tissue morphogenesis and may reveal molecular functions for this novel family of cell surface molecules. Understanding the cellular and molecular consequences of the Lrig3 mutation in SCC morphogenesis will not only highlight the role of such molecules in inner ear development, but will also give us insight into the development of the lateral canal as it compares to the better known development of the anterior and posterior canals. While the lateral semicircular canal of Lrig3 mutants is truncated, the anterior and posterior canals, including the lateral ampulae, remain unaffected. The specificity of this defect makes Lrig3 a particularly interesting protein for study since the lateral canal is the most frequently affected structure in numerous vestibular disorders, as observed for example in patients with CHARGE syndrome.