MOLECULAR CONTROL OF PATTERNING IN EARLY EAR DEVELOPMENT

早期耳朵发育中模式的分子控制

• 批准号: 6660619
• 负责人: KATE Francesca BARALD
• 金额: $ 4.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660619
• 关键词: axon; bone morphogenetic proteins; cell line; chick embryo; dendrites; developmental neurobiology; ear hair cell; embryo /fetus; epithelium; ganglions; gene expression; genetic models; inhibitor /antagonist; labyrinth; monoclonal antibody; otocyst /otolith; protein localization; quail; semicircular duct; tissue /cell culture

DESCRIPTION: (Adapted from the Investigator's Abstract) Inner ear development has been described as one of the most remarkable displays of precision microengineering in the vertebrate body" (Swanson et al, 1990). The long term goal of this research is to examine the function of genes that shape very early events in inner ear development in order to understand the mechanisms that produce many severe forms of congenital deafness. The experiments in this proposal examine the functional role of two genes expressed early in the development of the auditory system: bone morphogenetic protein 4 (BMP4) and noggin. The first and second specific aims test the hypothesis that the morphogen BMP4 expressed in localized cell foci in the otic epithelium and the BMP4 antagonist, noggin, expressed in the surrounding periotic mesenchyme, are responsible for modeling the semicircular canals (SCC) and sensory tissue (hair cells) within them. The chick is used as the model system in these studies because the levels of these important molecules can be manipulated in the chick system and the effects of altering the environment on auditory system development can he assessed. These experiments cannot he done in the mouse or zebra fish because BMP "knockout" mice and zebra fish mutations die before the inner ear forms, and therefore, any effects of altering the levels of expression of these genes can not be assessed. These experiments depend on misexpression of BMP4 and noggin, by implanting agarose beads bearing cells that express noggin or BMP4 into ectopic locations in the early developing inner ear. Noggin bead implants eliminate SCC selectively; BMP4 implants "rescue" the lost canals. The third specific aim tests the hypothesis that BMP/I expression is critical for sensory cell (hair cell and supporting cell) development in the inner ear. This laboratory has produced BMP4 expressing immortalized otocyst cells from the 9 day Immortomouse. These cells were used to "rescue" the loss of SCC in the preliminary experiments on which these studies are based. The cells in culture not only express hair cell markers in the order expected for hair cells in the embryo, but also serve as a model system to study the role of the relevant genes in the production of hair cell/supporting cells in the inner ear. Furthermore, a BMP-4-expressing IMO cell line also produces the statoacoustic ganglion (SAG) neurite outgrowth/survival factor that directs the emerging neurites of the SAG back to BMFP-expressing sensory cell targets in the developing otocyst. IMO cell lines can therefore be used in molecular studies to identify the molecular cascades that produce sensory cell lineages as well as the SAG neurite outgrowth factor.

描述：（改编自研究者摘要）内耳发育 被描述为最显著的精确性展示之一 脊椎动物体内的微工程”（Swanson等，1990）。长期 这项研究的目的是检查基因的功能， 内耳发育中的事件，以了解其机制 会导致许多严重的先天性耳聋。这个实验 这项提案研究了两个基因在胚胎发育早期表达的功能作用。 听觉系统的发育：骨形态发生蛋白4（BMP 4）和 noggin。第一个和第二个具体目标检验的假设， 骨形态发生蛋白4表达于耳上皮的局部细胞灶中， BMP 4拮抗剂noggin在周围的耳周间充质中表达， 负责半规管（SCC）和感觉组织（头发）建模 细胞）内。在这些研究中，鸡被用作模型系统 因为这些重要分子的水平可以在小鸡体内被操纵 环境变化对听觉系统的影响 发展可以评估。这些实验不能在老鼠身上进行， 斑马鱼因为BMP“敲除”老鼠而在斑马鱼突变前死亡 内耳形成，因此，任何改变 不能评估这些基因的表达。这些实验依赖于 BMP 4和头蛋白的错误表达，通过植入琼脂糖珠携带细胞 在发育早期表达头蛋白或BMP 4到异位位置 内耳Noggin珠植入物选择性消除SCC; BMP 4植入物 “拯救”失落的运河第三个具体目标检验了以下假设： BMP/I的表达对于感觉细胞（毛细胞和支持细胞）是至关重要的 内耳的发育。该实验室已经生产出表达BMP 4的 来自9天永生小鼠的永生化耳囊细胞。这些细胞被用来 为了“拯救”SCC的损失，在初步实验中，这些 研究是有根据的。培养中的细胞不仅表达毛细胞标记物， 胚胎中毛细胞的预期顺序，但也可以作为模型 系统来研究相关基因在头发产生中的作用 内耳的支持细胞。此外，表达BMP-4的IMO 细胞系还产生了耳听神经节（SAG）神经突 生长/生存因子，指导SAG的新兴神经突回到 表达BMFP的感觉细胞靶向发育中的耳囊。IMO细胞系 因此，可以用于分子研究，以确定分子级联 产生感觉细胞谱系以及SAG神经突生长因子。