EPH FAMILY RECEPTORS & LIGANDS IN THE HIPPOCAMPAL SYSTEM

轴突经常成束行进以到达它们的目标。在到达靶点后，轴突终末解束，迁移到拓扑学定义的位置，并与适当的靶神经元形成突触。调节这些过程的分子信号还不清楚。我们以前的研究表明，Eph家族酪氨酸激酶受体的成员，和他们的配体，Ephdns，在调节Ephcampat预测中发挥关键作用。Eph受体由EphA和EphB亚家族组成。我们的研究表明，EphA受体和配体分别在海马和其主要的皮质下靶区（外侧隔）中以相反的梯度表达，并且受体和配体之间的相互作用与EphA受体和配体之间的相互作用在海马和外侧隔中的表达相反。 配体梯度确定海马轴突终末的拓扑位置。相比之下，我们的初步研究表明，EphB型受体的成员，EphB 2，在海马体中均匀表达，和配体，ephrin-B3，在隔靶中均匀转录。ephrin-B3的暴露导致海马神经元的分散和海马轴突的去纤维化。缺失EphB 2受体的小鼠在隔膜中显示异常的轴突集束。这些观察倾向于EphA和EphB受体及其同源配体在调节海马轴突中功能不同的假设 靶向外侧隔，A型作为地形图标记，B型作为轴突解束的调节剂。为了验证这一假设，我们提出（1）阐明EphB受体和配体的空间和时间表达。(2)描述B-ephdns对离体海马轴突的作用。(3)分析EphB受体和配体的失活对海马轴突去纤维化的影响。(4)研究Eph受体功能的分子机制。拟议的研究将为轴突引导的分子机制提供新的见解，这可能有助于开发损伤后或阿尔茨海默病和帕金森病等疾病中再生神经回路的策略。

Axons travel frequently in bundles to reach their target. Upon arriving at the target, axon terminals defasciculate, migrate to topographicaJly defined positions, and form synapses with appropriate target neurons. Molecular signals regulating these processes are not well understood. Our previous studies indicate that members of the Eph family tyrosine kinase receptors, and their ligands, the ephdns, play critical roles in regulating hippocampat projections. The Eph receptors consist of EphA and EphB subfamilies. Our studies show that the EphA receptors and ligands are expressed in opposing gradients in the hippocampus and its major subcortical target, the lateral septum, respectively, and interactions between the receptor and the ligand gradients define topographic positions of hippocampal axon terminals. In contrast, our preliminary studies showed that a member of the EphB-type receptors, EphB2, is expressed uniformly in the hippocampus, and a ligand, ephrin-B3, is transcribed uniformly in the septal target. Exposure of ephrin-B3 leads to the dispersion of hippocampal neurons and defasciculation of hippocampal axons. Mice missing the EphB2 receptor show abnormal axon bundling in the septum. These observations tend to the hypothesis that EphA and EphB receptors and their cognate ligands are functionally distinct in regulating hippocampal axon targeting to the lateral septum, with the A-type as topographic mapping tags and the B-type as modulators of axon defasciculation. To test this hypothesis, we propose to (1) Elucidate the spatial and temporal expression of EphB receptors and ligands. (2) Delineate effects of B-ephdns on hippocampal axons in vitro. (3) Analyze effects of inactivation of EphB receptors and ligands on hippocampal axon defasciculation in vivo. (4) Examine the molecular mechanisms of Eph receptor functions. The proposed studies will provide new insights into the molecular mechanisms of axon guidance, which may facilitate development of strategies to regenerate neural circuits after injuries or in diseases such as Alzheimer's and Parkinson's diseases.