EPH FAMILY RECEPTORS & LIGANDS IN THE HIPPOCAMPAL SYSTEM

轴突经常成束地移动，以到达它们的目标。当到达靶点时，轴突终末脱叉，迁移到地形图上定义的位置，并与适当的靶神经元形成突触。调控这些过程的分子信号还没有被很好地理解。我们以前的研究表明，Eph家族的酪氨酸激酶受体及其配体Ephdns在调节海马区投射方面发挥着关键作用。Eph受体由EphA和EphB两个亚家族组成。我们的研究表明，EphA受体和配体分别以相反的梯度在海马区及其主要的皮质下靶点外侧隔中表达，并且受体和配体之间的相互作用 配基梯度定义了海马轴突终末的地形位置。相反，我们的初步研究表明，EphB型受体的一个成员EphB2在海马区统一表达，而配体ePhin-B3在隔区靶区统一转录。暴露于肾上腺素-B3可导致海马神经元的分散和海马轴突的散乱。缺少EphB2受体的小鼠在隔区表现出异常的轴突捆绑。这些观察结果倾向于一种假设，即EphA和EphB受体及其同源配体在调节海马轴突方面功能不同 以外侧隔为靶点，A型为地形图标记物，B型为轴突去散的调节器。为了验证这一假说，我们建议(1)阐明EphB受体和配体的空间和时间表达。(2)观察β-麻黄素对体外培养大鼠海马神经元轴突的影响。(3)体内分析EphB受体及其配体失活对海马轴突脱散的影响。(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，这可能有助于开发在损伤后或在阿尔茨海默氏症和帕金森氏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.