Eph-Ephrin Bidirectional Signaling in Visual Development

这项应用的中心是视觉系统的开发。目的是帮助我们更好地理解 视网膜神经节细胞(RGC)纤维如何靶向大脑，使眼睛与中枢神经系统硬连接，并导致 神经连接对视力很重要。此前在小鼠身上的研究表明，B亚类Eph 受体酪氨酸激酶及其膜锚定的肾上腺素配体参与三种不同的 RGC定位的方面：1)在视网膜内，RGC纤维进入视柄形成视神经 神经，2)视交叉，当RGC纤维选择投射到对侧或同侧时 关于双眼视觉，以及3)在上丘内，RGC纤维在地形图上映射到 眼睛的腹轴/背轴进入小丘的内侧/外侧轴。Eph受体与Ephin配体 是独特的分子，因为当Eph-EPhin在细胞与细胞接触的位置参与时，信号被转导 进入表达Eph的细胞(正向信号)和表达EPhin的细胞(反向信号)。这个 由Eph-EPhin相互作用传递的双向信号通常会导致细胞骨架的变化 这导致了排斥性或粘附性/吸引细胞迁移和引导事件。事实上，这三个人 RGC纤维中的Eph-Ephin信号的前述例子似乎产生了两种排斥 (例1和例2)或吸引(例3)事件。在这项应用中，我们计划进行活体实验 进一步剖析双向信号控制发育过程中连线的分子机制 视觉系统。我们将在小鼠生殖系中创造和分析新的突变和转基因结构 它们被设计成选择性地干扰前向和反向信令的特定组件。我们的 研究将进一步促进我们对Eph-Ephin分子机制的理解 双向信号控制着对视觉很重要的引导事件。因为视觉感对于 失明和失明的正常生活对受影响的个人和他们的 希望这项研究将提供重要的知识，有助于形成 未来潜在的再生疗法。

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.