Eph-Ephrin Bidirectional Signaling in Visual Development

描述（由申请人提供）：本申请以视觉系统的开发为中心。目的是帮助我们更好地了解视网膜神经节细胞（RGC）纤维如何靶向大脑，使眼睛与CNS硬连线，并实现对视觉重要的神经连接。先前在小鼠中的研究表明B亚类Eph受体酪氨酸激酶及其膜锚定的Ephrin配体参与RGC靶向的三个不同方面：1）在视网膜内，因为RGC纤维漏斗状地进入视柄以形成视神经，2）在视交叉处，因为RGC纤维选择向对侧或同侧投射以产生双眼视觉，和3）在上级丘内，因为RGC纤维地形图映射以将眼睛的腹侧/背侧轴镜像成丘中的内侧/外侧轴。Eph受体和肝配蛋白配体是独特的分子，因为在细胞-细胞接触位点处Eph-肝配蛋白接合时，信号被传递到表达Eph的细胞（正向信号传导）和表达肝配蛋白的细胞（反向信号传导）中。通过Eph-Ephrin相互作用转导的双向信号通常导致细胞骨架的改变，这导致排斥或粘附/吸引细胞迁移和引导事件。事实上，RGC纤维中Eph-Ephrin信号传导的三个前述实例似乎引起排斥（实例1和2）或吸引（实例3）事件。在这个应用中，我们计划在体内实验，以进一步剖析的分子机制，双向信号控制布线的发展中的视觉系统。我们将在小鼠生殖系中创建和分析新的突变和转基因构建体，这些突变和转基因构建体旨在选择性地干扰正向和反向信号传导的特定组分。我们的调查将进一步推进我们的理解的分子机制，Eph-Ephrin双向信号控制的指导事件重要的视觉。由于视力对正常生活至关重要，视力丧失和失明会对受影响的个人及其家庭造成严重后果，因此希望这项研究将提供重要的知识，可能有助于形成未来潜在再生疗法的基础。

DESCRIPTION (provided by applicant): This application centers on the development of the visual system. The goal is to help us better understand how retinal ganglion cell (RGC) fibers target into the brain to hard-wire the eye with the CNS and bring about the neural connections important for vision. Previous studies in mice have implicated the B-subclass Eph receptor tyrosine kinases and their membrane-anchored Ephrin ligands as participating in three distinct aspects of RGC targeting: 1) within the retina as the RGC fibers funnel into the optic stalk to form the optic nerve, 2) at the optic chiasm as RGC fibers make the choice to project contralaterally or ipsilaterally to bring about binocular vision, and 3) within the superior colliculus as RGC fibers topographically map to mirror the ventral/dorsal axis of the eye into a medial/lateral axis in the colliculus. The Eph receptors and Ephrin ligands are unique molecules in that upon Eph-Ephrin engagement at sites of cell-cell contact, signals are transduce into both the Eph-expressing cell (forward signaling) and the Ephrin-expressing cell (reverse signaling). The bidirectional signals transduced by Eph-Ephrin interactions generally lead to alterations in the cytoskeleton that result in either repulsive or adhesive/attractive cell migration and guidance events. Indeed, the three forementioned examples of Eph-Ephrin signaling in RGC fibers appears to bring about either repulsion (examples 1 and 2) or attraction (example 3) events. In this application, we plan in vivo experiments to further dissect the molecular mechanisms by which bidirectional signaling controls wiring of the developing visual system. We will create and analyze new mutations and transgenic constructs in the mouse germline that are designed to selectively interfer with specific components of forward and reverse signaling. Our investigations will further advance our understanding of the molecular mechanisms by which Eph-Ephrin bidirectional signaling controls guidance events important for vision. As the sense of sight is crucial for normal life with loss of vision and blindness posing severe consequences to affected individuals and their families, it is hope that this research will provide important knowledge that may help form the basis for potential regenerative therapies of the future.