Forming and Patterning the Vertebrate Inner Ear

脊椎动物内耳的形成和图案化

• 批准号: 6863005
• 负责人: GARY C SCHOENWOLF
• 金额: $ 39.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863005
• 关键词: biological models; chick embryo; developmental neurobiology; ectoderm; fibroblast growth factor; gene expression; gene induction /repression; genetic models; genetically modified animals; histogenesis; in situ hybridization; laboratory mouse; labyrinth; optic disk; polymerase chain reaction; quail

DESCRIPTION (provided by applicant): The early development of the inner ear occurs in three phases: formation of the otic placode, the earliest rudiment of the inner ear; morphogenesis of the otic placode, forming the otic pit (cup) and otocyst; and axis formation and regional patterning of the otocyst. Each phase is characterized by inductive interactions among different tissues. Although several signaling systems have been implicated in the control of these phases, Fibroblast Growth Factor (FGF) signaling clearly plays a critical role and is the focus of this proposal. This project combines the broad technical and scientific expertise of two investigators and uses two animal models to examine the cellular, molecular and genetic control of early inner ear development. To study the formation and patterning of the rudiments of the inner ear we will conduct experiments designed to achieve three specific aims. First, using tissue recombination experiments and modern molecular techniques, we will establish how fgf19, Wnt8c and fgf3, critical factors that we identified in the previous project period in formation of the otic placode, are localized in the cephalic paraxial mesoderm of the early chick embryo. This will allow us to determine how the rudiments of the inner ear are positioned within the head of the developing embryo. Second, we will determine the roles of Fgf4 and Fgf8 in formation of the rudiments of the inner ear. Expression studies, experimental embryology and genetic analyses from the previous project period strongly implicated these two factors in inner ear development. Third, we will determine and compare the roles of Fgf16 and Fgf3 in the patteming of the rudiments of the inner ear in mouse and chick. Expression studies and analyses of Fgf3/Fgf10 mutant embryos from the previous project period led to the hypothesis that these two factors play essential roles in formation of the otic axes and/or specification of cell types within the developing inner ear. This hypothesis will be rigorously tested taking advantage of the unique strengths of the two animal model systems that we employ in our studies. By achieving these three aims, we will gain important new information on the normal development of the inner ear and the FGFs that regulate its formation and patterning. Additionally, our studies will furnish insight into mechanisms by which these developmental processes go awry, underlying the formation of serious birth defects of the auditory system in humans.

描述（由申请人提供）：内耳的早期发育分为三个阶段：耳基板（内耳最早的雏形）的形成;耳基板的形态发生，形成耳窝（杯）和耳囊;耳囊的轴形成和区域图案。每个阶段的特征在于不同组织之间的诱导相互作用。虽然有几个信号系统已经涉及到这些阶段的控制，成纤维细胞生长因子（FGF）信号显然起着关键作用，是这个建议的重点。该项目结合了两位研究人员广泛的技术和科学专业知识，并使用两种动物模型来研究早期内耳发育的细胞、分子和遗传控制。为了研究内耳雏形的形成和模式，我们将进行旨在实现三个特定目标的实验。首先，使用组织重组实验和现代分子技术，我们将建立如何fgf 19，Wnt 8 c和fgf 3，我们确定在前一个项目期间在耳基板的形成中的关键因素，是本地化的早期鸡胚的头部近轴中胚层。这将使我们能够确定内耳的雏形如何定位在发育中的胚胎的头部内。其次，我们将确定Fgf 4和Fgf 8在内耳雏形形成中的作用。表达研究，实验胚胎学和遗传分析，从以前的项目期间强烈暗示这两个因素在内耳发育。第三，我们将确定和比较Fgf 16和Fgf 3在小鼠和鸡内耳雏形模式化中的作用。来自先前项目期的Fgf 3/Fgf 10突变胚胎的表达研究和分析导致了这两个因子在耳轴的形成和/或发育中内耳内细胞类型的特化中起重要作用的假设。我们将利用我们研究中采用的两种动物模型系统的独特优势，对这一假设进行严格的检验。通过实现这三个目标，我们将获得有关内耳正常发育和调节其形成和模式的FGF的重要新信息。此外，我们的研究将深入了解这些发育过程出错的机制，这些机制是人类听觉系统严重先天缺陷形成的基础。