Lrig interactions with ErbB pathways in the inner ear

描述（由申请人提供）：听觉和平衡的感知起源于内耳的复杂耳内。耳蜗的正确形成是检测声音所必需的，而前庭器官的正确形成和定向是平衡所必需的。对促进内耳形态发生的基因的了解将为许多人类听力和平衡障碍的根本原因提供见解。我们已经确定了一个新的成员的IG超家族，Lrig3，这是必要的前庭系统的正确形成。Lrig3突变小鼠具有截短的外半规管（SCC），因此表现出盘旋行为。对这些突变体的详细分析将揭示Lrig3在耳道形成中的功能，并可能揭示其他功能，因为所有三个Lrig基因在内耳和大脑中以重叠模式表达。其中一个家族成员Lrig1与ErbB受体家族结合并调节其降解，这增加了Lrig3也通过Erb途径发挥作用的可能性。这一假设将通过表达研究和体外生物化学测定进行检验。这些研究将阐明复杂组织形态发生的细胞机制，并可能揭示这种新型细胞表面分子家族的分子功能。了解SCC形态发生中Lrig3突变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，因为它与更好地了解前管和后管的发育相比。虽然Lrig3突变体的外半规管被截断，但前半规管和后半规管，包括外侧壶腹，保持不受影响。这种缺陷的特异性使得Lrig3成为研究的特别感兴趣的蛋白质，因为侧管是许多前庭疾病中最常受影响的结构，例如在CHARGE综合征患者中观察到的。

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.