EPH FAMILY RECEPTORS IN THE HIPPOCAMPOSEPTAL SYSTEM

海马中隔系统中的 EPH 家族受体

• 批准号: 6301939
• 负责人: RENPING ZHOU
• 金额: $ 14.52万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 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 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301939
• 关键词: affinity labeling; brain mapping; brain septal area; cell line; developmental neurobiology; gene expression; genetic promoter element; genetically modified animals; glia; growth factor receptors; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; ligands; mixed tissue /cell culture; neuronal transport; neurotrophic factors; northern blottings; receptor expression; tubulin; affinity labeling; brain mapping; brain septal area; cell line; developmental neurobiology; gene expression; genetic promoter element; genetically modified animals; glia; growth factor receptors; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; ligands; mixed tissue /cell culture; neuronal transport; neurotrophic factors; northern blottings; receptor expression; tubulin

Topographic projection is a general feature of brain architecture, and appears to be critical for appropriate coding and processing of information. The hippocampus and septum, which have been the focus of intense interest, since these structures play a central roles in learning and memory, are interconnected topographically. Although their topographic connections have been known for nearly two decades, and the topography may be critical for cognitive functions, the molecular basis for the topographic projection is unknown. The long term goal of this study is to elucidate the molecular mechanisms of axonal targeting in the hippocamposeptal system. It has been proposed by Roger Sperry that topographic mapping is accomplished by matching gradients of chemoaffinity labels on the pre-synaptic and postsynaptic neurons. Consistent with this proposal, we have shown that Bsk, an eph family receptor, and its ligands are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, we have shown that, one of the ligands, Elf-1, selectively inhibited the growth of topographically incorrect but allowed the growth of hippocampal neurites. These observations led to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topographic mapping. Several predictions can be made based on this hypothesis: 1, the eph family ligands and receptors are expressed in proper gradients at the time of topographic mapping; 2, the ligands inhibit or support the growth of axons from appropriate regions of the hippocampus in vitro; 3. changing the gradients of expression disturbs the topographic projection in vivo. to test these predictions, we propose to examine the spatial and temporal patterns of expression of eph ligands and receptors in the hippocamposeptal system, and study the biological actions of the ligands on the hippocampal neurons in vitro. In additions, as critical tests for the roles of expression gradients of the eph molecules, we plan to take two complementary approaches to alter Bsk expression and function in vivo. First, we will inject a soluble eph ligand, A1-1/rags, which serves as an inhibitor for Bsk or related receptors, into developing mouse brains; Second, we will over-express Bsk using Talpha1 neuron-specific tubulin promoter, which generates high levels of uniform expression, in transgenic mice. The effect of these alterations on the hippocamposeptal topographic projection will be examined using axonal tracing techniques. These studies will help to understand how the output pathways of the hippocampus are organized and may shed light on the mechanism of learning and memory, as well as diseases affecting these processes.

地形投影是大脑架构的一般特征， 似乎对于适当的编码和处理至关重要 信息。海马和隔膜，这一直是 激烈的兴趣，因为这些结构在学习中起着核心作用 和内存，在地形上是相互联系的。虽然它们的地形 联系已有近二十年了，地形可能 对于认知功能至关重要，这是分子基础 地形投影未知。这项研究的长期目标是 阐明轴突靶向的分子机制 海马系统。罗杰·斯佩里（Roger Sperry）提出了 地形映射是通过匹配化学亲和力梯度来完成的 在突触前和突触后神经元上的标签。与此一致 提案，我们已经证明了BSK，EPH家族受体及其配体 在海马和 目标，成人大脑中的侧隔隔隔膜。此外，我们已经显示 其中一种配体Elf-1有选择地抑制 地形不正确，但允许海马神经突的生长。 这些观察结果导致了以下假设：EPH家族受体和 配体充当海马地形的化学亲和力标签 映射。基于此假设可以做出几个预测：1， EPH家族配体和受体以适当的梯度表达 地形映射的时间； 2，配体抑制或支持生长 来自海马的适当区域的轴突体外； 3。更改 表达的梯度打扰了体内的地形投影。 为了测试这些预测，我们建议检查空间和时间 EPH配体和受体表达的模式 海马系统系统，研究配体的生物学作用 在体外的海马神经元上。此外，作为对的关键测试 EPH分子的表达梯度的作用，我们计划采用 两种互补的方法改变了体内BSK表达和功能。 首先，我们将注入可溶性EPH配体A1-1/rags，它用作 BSK或相关受体的抑制剂，发展为发育小鼠大脑； 其次，我们将使用TALPHA1神经元特异性微管蛋白过度表达BSK 在转基因中产生高水平的均匀表达的启动子 老鼠。这些改动对海马膜地形的影响 投影将使用轴突跟踪技术进行检查。这些研究 将有助于了解海马的输出途径 有组织并可能阐明学习和记忆的机制， 以及影响这些过程的疾病。