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。其目的是帮助我们更好地理解视网膜神经节细胞（RGC）纤维如何进入大脑，将眼睛与中枢神经系统硬连接起来，并实现对视力至关重要的神经连接。先前对小鼠的研究表明，b亚类Eph受体酪氨酸激酶及其膜锚定Ephrin配体参与了RGC靶向的三个不同方面：1)在视网膜内，因为RGC纤维漏斗进入视柄形成视神经；2)在视交叉处，因为RGC纤维选择对侧或同侧投射，从而产生双目视觉；3)在上丘内，因为RGC纤维在地形上映射，将眼睛的腹/背轴镜像成丘的内/外侧轴。Eph受体和Ephrin配体是独特的分子，当Eph-Ephrin在细胞-细胞接触位点结合时，信号被转导到表达Eph的细胞（正向信号传导）和表达Ephrin的细胞（反向信号传导）。epf - ephrin相互作用传递的双向信号通常会导致细胞骨架的改变，从而导致排斥或粘附/吸引的细胞迁移和引导事件。事实上，前面提到的三个在RGC纤维中的epf - ephrin信号的例子似乎带来了排斥（例子1和2）或吸引（例子3）事件。在这个应用中，我们计划进行体内实验，进一步剖析双向信号控制发育中的视觉系统的分子机制。我们将在小鼠种系中创建和分析新的突变和转基因结构，这些突变和转基因结构旨在选择性地干扰正向和反向信号的特定成分。我们的研究将进一步推进我们对epf - ephrin双向信号控制视觉重要指导事件的分子机制的理解。由于视力对正常生活至关重要，视力丧失和失明会给患者及其家人带来严重后果，因此希望这项研究将提供重要的知识，可能有助于为未来潜在的再生疗法奠定基础。

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.