Eph-Ephrin Bidirectional Signaling in Visual Development

描述(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了解视网膜神经节细胞(RGC)纤维是如何进入大脑的，从而将眼睛与中枢神经系统连接起来，并带来对视觉重要的神经连接。以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的Ephin配体参与了RGC靶向的三个不同方面：1)在视网膜内，RGC纤维进入视柄形成视神经；2)在视交叉处，RGC纤维选择双侧或同侧投射而产生双眼视觉；3)在上丘内，RGC纤维在地形图上映射以将眼睛的腹背轴映射到视丘的内侧轴。Eph受体和Ewitin配体是独特的分子，因为当Eph-EPhin在细胞与细胞接触的位置发生作用时，信号被转导到表达Eph的细胞(正向信号)和EPhin表达的细胞(反向信号)。Eph-EPhin相互作用传递的双向信号通常会导致细胞骨架的改变，从而导致排斥或粘连/吸引的细胞迁移和引导事件。事实上，上述RGC纤维中的Eph-EPhin信号的三个例子似乎引起排斥(例1和例2)或吸引(例3)事件。在这一应用中，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连接的分子机制。我们将在小鼠生殖系中创建和分析新的突变和转基因结构，这些结构旨在选择性地干扰正向和反向信号的特定组成部分。我们的研究将进一步促进我们对Eph-Ephin双向信号控制视觉重要引导事件的分子机制的理解。由于视力对正常生活至关重要，失明和失明会对受影响的个人及其家人造成严重后果，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的再生疗法的基础。

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.