Regulating dorsoventral polarity within the inner ear

调节内耳内的背腹极性

• 批准号: 6673551
• 负责人: DOUGLAS J EPSTEIN
• 金额: $ 32.45万
• 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/6673551
• 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; 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调节我们的听觉和平衡感。最近在确定人类遗传性耳聋和前庭疾病的一些原因方面取得了进展;然而，对协调内耳发育的遗传途径的详细了解仍然有限。通过识别调节内耳形态发生的遗传网络，我们对耳发育和疾病之间关系的理解应该会有所提高。听觉（耳蜗）和平衡（半规管、椭圆囊和球囊）的主要组成部分分别由共同的双侧结构（耳囊）的腹侧和背侧生长物形成。内耳组织成听觉和前庭组件依赖于耳泡内的基因表达的局部模式。已知周围组织影响耳泡的区室化，但参与信号仍不清楚。脊索和底板是分泌蛋白质Sonic hedgehog（Shh）的来源，其在短距离和长距离信号传导事件中起作用以促进腹侧神经管和旁轴结构中祖细胞的生长和分化。在没有Shh的情况下，腹侧耳衍生物，包括耳蜗管和耳蜗前庭神经节未能发展。Shh -/-胚胎中内耳缺陷的起源可归因于先前与耳蜗、神经元和软骨形成谱系的规范有关的许多基因表达的改变。虽然在耳上皮中检测到Shh信号传导的作用，但是包括耳周间充质和神经管的邻近组织也是Shh作用的靶。 这引起了人们对Shh信号在影响内耳发育的每个组织中的相对贡献的质疑。在这项建议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。内耳发育中Hedgehog（Hh）信号传导的时间和空间要求将通过在影响耳泡的每个组织中有条件地失活Smoothened（所有Hh信号的重要换能器）来解决。 还提出了实验，以确定下游效应的Shh信号在耳发育。最后，尽管初步了解听觉细胞的命运是如何指定的，很少有人知道的外在线索，建立前庭（背）结构的耳泡。 采用转基因方法将特定途径抑制剂引入背侧耳囊，以及评估候选背侧因子中的小鼠突变体，应有助于我们全面了解极性是如何沿沿着内耳背腹轴建立的。