MOLECULAR CONTROL OF PATTERNING IN EARLY EAR DEVELOPMENT

描述：(改编自《调查者摘要》)内耳发育 被描述为最杰出的精确度展示之一 脊椎动物体内的微工程学“(Swanson等人，1990)。 这项研究的目标是检查很早就形成的基因的功能。 内耳发育中的事件，以了解 会产生许多严重的先天性耳聋。这里面的实验 研究早期表达的两个基因的功能作用。 听觉系统的发展：骨形态发生蛋白4和 诺金。第一个和第二个具体目标检验了这样的假设 形态发生蛋白BMP4在耳上皮细胞内的定位表达 BMP4拮抗剂noggin在周围骨膜间充质中表达 负责半规管(SCC)和感觉组织(头发)的建模 细胞)在它们内部。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在雏鸟体内是可以操纵的 系统与环境变化对听觉系统的影响 发展是可以评估的。这些实验不能在小鼠身上或在 斑马鱼是因为BMP基因敲除的小鼠和斑马鱼的突变在死亡之前 内耳形成，因此，改变水平的任何影响 这些基因的表达无法评估。这些实验依赖于 通过植入带有琼脂糖珠的细胞获得BMP4和noggin的错误表达 在发育早期将noggin或BMP4表达到异位 内耳。Noggin珠状植入物选择性消除鳞癌；BMP4植入物 “拯救”失落的运河。第三个具体目标是检验这样一个假设 BMP/I的表达对感觉细胞(毛细胞和支持细胞)至关重要 内耳的发育。这个实验室已经生产出BMP4表达 从第9天的永生化小鼠中分离出永生化耳囊细胞。这些细胞被用来 在初步实验中“挽救”SCC的损失，这些 研究是基于。培养中的细胞不仅表达毛细胞标志物 毛细胞在胚胎中的预期顺序，也可以作为一个模型 研究相关基因在毛发生产中的作用的系统 内耳中的细胞/支持细胞。此外，表达BMP-4的IMO 细胞系还产生状态声神经节(SAG)轴突 将SAG中新生的神经突起引导回 在发育中的耳囊中表达BMFP的感觉细胞靶点。国际海事组织细胞系 因此可用于分子研究以识别分子级联 产生感觉细胞谱系和SAG轴突生长因子。

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.