Molecular Basis For The Morphogenesis Of The Inner Ear

内耳形态发生的分子基础

• 批准号: 7297966
• 负责人: Doris Wu
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7297966
• 关键词: Molecular; Basis; Morphogenesis; Inner; Ear

Our major accomplishments this year are in the following areas: 1) Role of Noggin in ear development Noggin is a secreted molecule that functions as an antagonist of Bone morphogenetic proteins (BMP) by binding to BMPs and prevent them from activating their receptors. In humans, mutations of the NOGGIN gene is associated with several disorders that are characterized by synotosis and conductive hearing loss. We analyzed the inner ears of Noggin knockout mutant embryos and we show that the mutant inner ears have malformations in both the membranous and bony labyrinths. We provided evidence that the membranous labyrinth defects are due to the misalignment of the rhombomeres and otocysts positions during early stages of embryogenesis. Malformation of the cochlear duct is the most prevalent membranous phenotype in these mutants. In addition, there is an increase in the size of the bony labyrinth. The increase in chondrogenesis within the bony labyrinth is most likely due to an unopposed BMP signaling in the peri-otic mesenchyme. Our preliminary results also suggest that some of the heterozygous Noggin mutants display hearing loss, similar to human patients with NOGGIN mutations. 2) Role of Gli proteins in inner ear development Our previous studies have shown that Sonic hedgehog emanated from either the floor plate or the notochord is a major factor in dictating ventral patterning of the inner ear. To address how Shh mediates this effect, we analyzed inner ears of mouse embryos with various genetic combinations of mutant alleles of Shh, Gli2, and/or Gli3. Our results show that different inner ear structures along the dorsal ventral axis is established by different levels of Gli activator and repressor activities, regulated by different levels of Shh. The most ventral region of the inner ear, the distal cochlear duct, requires Gli activator functions mediated by high levels of Shh signaling. The formation of the middle region of the inner ear, the saccule and the proximal region of the cochlear duct, requires moderate levels of Shh signaling to either alleviate the Gli3 repressor activities or to activate some Gli activators. On the other hand, Gli3 repressor activity is essential for the proper formation of the dorsal vestibular structures. Together, these results indicate the importance of Shh in mediating balanced levels of Gli activator and repressor activities for the formation of the inner ear.

我们今年的主要成就是以下领域： 1）Noggin在耳朵发育中的作用 Noggin是一种分泌的分子，通过与BMP结合并防止它们激活其受体，可以充当骨形态发生蛋白（BMP）的拮抗剂。在人类中，Noggin基因的突变与多种疾病有关，这些疾病的特征是出色的和导电性听力损失。我们分析了Noggin基因敲除突变体胚胎的内耳，我们表明突变体的内耳在膜和骨迷宫中均具有畸形。我们提供了证据表明，膜的迷宫缺陷是由于胚胎发生早期阶段的菱形和耳囊位置的错位。人工耳蜗的畸形是这些突变体中最普遍的膜表型。此外，骨迷宫的大小也有所增加。骨迷宫内的软骨发生的增加很可能是由于围巾间充质中无反对的BMP信号传导所致。我们的初步结果还表明，一些杂合的Noggin突变体显示出听力损失，类似于人类的Noggin突变患者。 2）GLI蛋白在内耳发育中的作用 我们以前的研究表明，从地板板或脊索中散发出的声音刺猬是决定内耳腹侧图案的主要因素。为了解决SHH如何介导这种效应，我们分析了小鼠胚胎的内耳，并用SHH，GLI2和/或GLI3突变等位基因的各种遗传组合分析了小鼠胚胎的内耳。我们的结果表明，沿背腹侧轴的不同内耳结构是由不同水平的GLI激活剂和阻遏活性建立的，该活动由不同水平的SHH调节。内耳最腹侧区域，远端耳蜗，需要由高水平的SHH信号传导介导的GLI激活剂。内耳中间区域，耳蜗管的近端区域的形成需要中等水平的SHH信号传导，以减轻GLI3抑制剂活性或激活某些GLI激活剂。另一方面，GLI3阻遏活性对于正确形成背侧前庭结构至关重要。总之，这些结果表明，SHH在介导平衡的GLI激活剂和阻遏物活性中的重要性对于内耳的形成。