Eph-Ephrin Bidirectional Signaling in Visual Development

视觉发育中的 Eph-Ephrin 双向信号传导

• 批准号: 7080035
• 负责人: MARK J HENKEMEYER
• 金额: $ 39.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080035
• 关键词: axon; ephrins; ligands; receptor; tyrosine

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.

描述（由申请人提供）：该申请以视觉系统的开发为中心。目标是帮助我们更好地了解视网膜神经节细胞 (RGC) 纤维如何定位到大脑，将眼睛与中枢神经系统硬连线，并建立对视觉重要的神经连接。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 RGC 靶向的三个不同方面：1）在视网膜内，因为 RGC 纤维漏斗状进入视柄形成视神经；2）在视交叉处，因为 RGC 纤维选择向对侧或同侧投射，以产生视神经。 关于双眼视觉，3）在上丘内，因为 RGC 纤维在地形上映射以将眼睛的腹侧/背侧轴镜像到丘中的内侧/外侧轴。 Eph 受体和 Ephrin 配体是独特的分子，因为 Eph-Ephrin 在细胞与细胞接触位点结合后，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）中。 Eph-Ephrin 相互作用转导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/吸引细胞迁移和引导事件。事实上，前面提到的 RGC 纤维中 Eph-Ephrin 信号传导的三个例子似乎会带来排斥（实施例 1 和 2）或吸引（实施例 3）事件。在此应用中，我们计划进行体内实验，以进一步剖析双向信号控制发育中视觉系统接线的分子机制。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成分。我们的研究将进一步加深我们对 Eph-Ephrin 双向信号传导控制对视觉重要的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，视力丧失和失明会给受影响的个人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，有助于为未来潜在的再生疗法奠定基础。