EPH FAMILY RECEPTORS IN THE HIPPOCAMPOSEPTAL SYSTEM

地形投影是脑结构的一般特征，并且 似乎是适当编码和处理的关键 信息。海马体和隔膜，这一直是 浓厚的兴趣，因为这些结构在学习中起着核心作用 和记忆，在拓扑上是相互联系的。尽管他们的地形 近二十年来，人们已经知道了连接，而地形可能 对认知功能至关重要，这是 地形投影是未知的。这项研究的长期目标是 阐明轴突靶向的分子机制 海马隔系统。罗杰·斯佩里曾提议 地形测绘是通过匹配化学亲和力的梯度来完成的 突触前和突触后神经元上的标记。与此一致 建议，我们已经证明了BSK，一种Eph家族受体，及其配体 在海马体中以互补的梯度表达 目标是成人大脑的外侧隔膜。此外，我们已经展示了 其中一种配体Elf-1选择性地抑制了肿瘤细胞的生长 地形图不正确，但允许海马神经突起生长。 这些观察结果导致假设Eph家族受体和 配体作为海马隔地形图的化学亲和性标记 映射。基于这一假设，可以做出几个预测：1、 Eph家族的配体和受体以适当的梯度在 地形测绘的时间；2、配体抑制或支持生长 海马区适当区域轴突的体外培养；3.改变 表达的梯度干扰了体内的地形图投影。 为了测试这些预测，我们建议检查空间和时间 Eph配体和受体在血管内皮细胞中的表达 ，并研究配体的生物学作用 在体外培养的海马神经元上。此外，作为对 Eph分子的表达梯度的作用，我们计划采取 两种互补的方法在体内改变BSK的表达和功能。 首先，我们将注射一种可溶性的Eph配体A1-1/RAGS，它作为一种 BSK或相关受体的抑制剂，进入发育中的小鼠大脑； 其次，我们将使用Talpha1神经元特异性微管蛋白过度表达BSK 启动子，在转基因中产生高水平的统一表达 老鼠。这些改变对海马隔区地形图的影响 投射将使用轴突追踪技术进行检查。这些研究 将有助于理解海马体的输出通路是如何 并可能阐明学习和记忆的机制，如 以及影响这些过程的疾病。

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.