Regulating dorsoventral polarity within the inner ear

调节内耳内的背腹极性

• 批准号: 7087017
• 负责人: DOUGLAS J EPSTEIN
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087017
• 关键词: biological signal transduction; cell differentiation; cell surface receptors; cochlea; developmental genetics; functional /structural genomics; gene expression; gene targeting; genetically modified animals; histogenesis; integrase; laboratory mouse; labyrinth; mesenchyme; otocyst /otolith; rhombencephalon; sonic hedgehog gene /protein; transcription factor

DESCRIPTION (provided by applicant): The auditory and vestibular structures of the inner ear mediate our senses of hearing and balance, respectively. Recent progress has been made in identifying some of the causes of hereditary forms of deafness and vestibular disease in humans; however, a detailed understanding of the genetic pathways coordinating inner ear development remains limited. By identifying the genetic networks regulating inner ear morphogenesis, our understanding of the association between otic development and disease should improve. The principal components for hearing (the cochlea) and balance (the semicircular canals, utricle and saccule) are formed from ventral and dorsal outgrowths, respectively, of a common bilateral structure, the otocyst. Organization of the inner ear into auditory and vestibular components is dependent on localized patterns of gene expression within the otic vesicle. Surrounding tissues are known to influence compartmentalization of the otic vesicle, yet the participating signals remain unclear. The notochord and floor plate are sources of the secreted protein Sonic hedgehog (Shh) that functions in both short and long range signaling events to promote growth and differentiation of progenitor cells in the ventral neural tube and paraxial structures. In the absence of Shh, ventral otic derivatives including the cochlear duct and cochleovestibular ganglia fail to develop. The origin of the inner ear defects in Shh -/- embryos can be attributed to alterations in the expression of a number of genes previously implicated in the specification of cochlear, neuronal and chondrogenic lineages. Although the effects of Shh signaling are detected in the otic epithelium, adjacent tissues including the periotic mesenchyme and neural tube are also targets of Shh action. This brings into question the relative contribution of Shh signaling in each of the tissues impacting on inner ear development. Experiments outlined in this proposal are aimed at elucidating the mechanism by which Shh specifies auditory cell fates in the ventral otocyst. The temporal and spatial requirements of Hedgehog (Hh) signaling in inner ear development will be addressed by the conditional inactivation of Smoothened, an essential transducer of all Hh signals, in each of the tissues impacting on the otic vesicle. Experiments to identity the downstream effectors of Shh signaling in otic development are also proposed. Finally, despite preliminary insights into how auditory cell fates are specified, little is known of the extrinsic cues that establish vestibular (dorsal) structures in the otic vesicle. Introduction of specific pathway inhibitors into the dorsal otocyst using transgenic approaches as well as the assessment of mouse mutants in candidate dorsalizing factors should contribute towards our overall understanding of how polarity is established along the dorsoventral axis of the inner ear.

描述（由申请人提供）：内耳的听觉和前庭结构分别介导了我们的听力和平衡感。在确定人类遗传形式的一些遗传形式和前庭疾病的原因方面取得了最新进展。但是，对协调内耳发育的遗传途径的详细理解仍然有限。通过识别调节内耳形态发生的遗传网络，我们对耳朵发育与疾病之间的关联的理解应得到改善。听力的主要成分（耳蜗）和平衡（半圆形管，肠子和囊泡）分别由腹侧和背侧产物形成，分别是相结合的双侧双侧结构，即耳状结构。内耳组织成听觉和前庭成分取决于耳囊中基因表达的局部模式。已知周围的组织会影响耳囊的隔室化，但参与信号仍不清楚。脊索和地板板是分泌的蛋白质刺猬（SHH）的来源，在短距离和远程信号事件中起作用，以促进腹神经管和副结构中祖细胞的生长和分化。在没有SHH的情况下，包括耳蜗和耳目联腹神经节在内的腹侧耳衍生物无法发育。 SHH - / - 胚胎中内耳缺陷的起源可以归因于先前与人工耳蜗，神经元和软骨谱谱系相关的许多基因表达的改变。尽管在耳上皮中检测到SHH信号的作用，但包括毛毛虫间充质和神经管在内的相邻组织也是SHH作用的靶标。 这使SHH信号在每种影响内耳发育的组织中的相对贡献都引起了质疑。该提案中概述的实验旨在阐明SHH指定腹侧耳囊中听觉细胞命运的机制。刺猬（HH）信号在内耳发育中的时间和空间需求将通过有条件地灭活，这是所有HH信号的基本换能器的有条件灭活，这是所有HH信号的必不可少的换能器，在每个影响眼球囊泡的组织中。 还提出了对身份的实验。最后，尽管对如何指定听觉细胞的命运有初步的见解，但对在耳囊中建立前庭（背侧）结构的外部线索知之甚少。 使用转基因方法以及候选因子中小鼠突变体评估小鼠突变体的特定途径抑制剂在背腹性囊肿中的引入应有助于我们对沿着内耳的背腹轴建立极性的整体理解。