EPH MOLECULES IN HIPPOCAMPAL TOPOGRAPHIC PROJECTIONS

本研究的长期目标是阐明 轴突靶向机制的研究进展 它 罗杰·斯佩里（Roger Sperry）提出， 通过匹配梯度的化学亲和性标签上， 突触前和突触后神经元。 根据这一提议， PirnUNR研究人员已经表明，Bsk，一种Eph家族受体， 和它的配体在互补梯度中表达， 海马和目标，成人大脑中的外侧隔。 此外，他选择性地展示了这些配体之一，Elf-1， 抑制了地形不正确的神经突的生长，但允许 正确的海马神经突起的生长。 这些观察雪橇 Eph家族受体和配体作为 化学亲和性标记，以用于绘制冠状动脉中隔地形图。 根据这一假设可以做出几个预测：1）Eph 家族配体和受体以相对梯度表达， 2）配体抑制或支持 在体外从海马的适当区域生长轴突; 3)改变表达的梯度扰乱了 体内投射 为了验证这些预测，研究人员提出， 检测Eph表达的时空模式， 配体和受体的camposeptal系统，并研究 配体对海马神经元的生物学作用。 此外，作为对表达梯度的作用的关键测试， 为了制备EPH分子，申请人计划将两个互补的 改变Bsk在体内的表达和功能的方法。 首先，他会 注射作为抑制剂可溶性Eph配体A1-1/RAGS Bsk或相关受体，进入发育中的小鼠大脑。 二是他 将使用Tisa 1神经元特异性微管蛋白启动子过表达Bsk， 其在转基因小鼠中产生高水平的均匀表达。 这些改变对海马地形图的影响 将使用轴突追踪技术检查投射。 这些 研究将有助于了解细胞的输出途径 海马是有组织的，可能揭示了 学习和记忆，以及影响这些过程的疾病。

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 presynaptic and postsynaptic neurons. Consistent with this proposal, the pirncipal investigator has shown that Bsk, an eph family receptor, and its ligand are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, he has shown one of these ligands, Elf-1, selectively inhibited the growth of topographically incorrect neurites, but allowed the growth of correct hippocampal neurites. These observation sled to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topograph mapping. Several predictions can be made based on this hypothesis: 1) the eph family ligands and receptors are expressed in propoer gradients at the time of topographic maping; 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, the investigator proposed 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 addition, as critical tests for the roles of expression gradients of the eph molecules, the applicant plans to take two complementary approaches to alter Bsk expression and function in vivo. First, he will inject a soluble eph ligand, A1-1/RAGS, which serves as an inhibitor for Bsk or related receptors, into developing mouse brain. Second, he will overexpress Bsk using Talphal neuron-specific tublin promoter, which generates high levels of uniform expression, in transgenic mice. The effects of these alterations on the hippocampal 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 mechanisms of learning and memory, as well as diseases affecting these processes.