Eph-Ephrin Bidirectional Signaling in Visual Development

视觉发育中的 Eph-Ephrin 双向信号传导

基本信息

批准号：
7777265
负责人：
MARK J HENKEMEYER
金额：
$ 37.73万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7777265
关键词：
Address Adhesives Affect Affinity Animal Model Axon Binding Binocular Vision Biochemical Blindness Brain C-terminal Cell membrane Cells Complex Coupling Cues Cytoplasmic Tail Cytoskeleton Data Development Dorsal Eph Family Receptors EphB2 Receptor Ephrin-B1 Ephrin-B2 Ephrin-B3 Ephrins Event Exhibits Eye Family Fiber Future GTP-Binding Proteins Gene Targeting Genes Genetic Goals Growth Cones Individual Investigation Ipsilateral Knowledge Laboratories Lateral Lead Life Ligands Maps Medial Mediating Membrane Molecular Mus Mutation NR1 NMDA receptor Nervous system structure Optic Chiasm Optic Disk Optic Nerve Phosphorylation Play Protein Tyrosine Kinase Proteins Publishing Receptor Protein-Tyrosine Kinases Research Research Personnel Research Project Grants Retina Retinal Ganglion Cells Role Side Signal Transduction Site Src homology 2 domain-containing, transforming protein 1 Transgenic Organisms Tyrosine Tyrosine Kinase Domain Tyrosine Phosphorylation Vision Visual system structure axon guidance base cell motility cell type cellular transduction design fibroglycan in vivo intercellular communication optic stalk prevent programs protein protein interaction receptor regenerative therapy relating to nervous system research study superior colliculus Corpora quadrigemina vision development

项目摘要

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.

该应用以视觉系统的开发为中心。目标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，以用中枢神经系统硬化眼睛并带来神经联系对视觉很重要。以前在小鼠中的研究牵涉到B级eph 受体酪氨酸激酶及其膜锚定的埃弗林配体参与三个不同的 RGC靶向的各个方面：1）在视网膜内RGC纤维漏斗到视神经茎上以形成视神经器神经，2）在视觉上，RGC纤维可以选择对侧或同侧进行投影关于双眼视力，3）在上丘中，当RGC纤维在地形上绘制以镜像眼睛的腹侧/背轴成凸孔中的内侧/侧轴。 EPH受体和Ephrin配体是独特的分子进入表达EPH的细胞（正向信号传导）和表达ephrin的细胞（反向信号传导）。这以弗所蛋白相互作用转导的双向信号通常会导致细胞骨架的改变这会导致排斥或粘合剂/有吸引力的细胞迁移和指导事件。确实，三个 RGC纤维中Eph-磷信号传导的前置示例似乎会引起任何一种排斥（示例1和2）或吸引力（示例3）事件。在此应用中，我们计划体内实验进一步剖析双向信号传导控制发育的接线的分子机制视觉系统。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旨在选择性地干扰正向和反向信号的特定组件。我们的调查将进一步提高我们对弗氏蛋白的分子机制的理解双向信号传导控制对视觉重要的指导事件。因为视觉对正常的生活，视力和失明丧失，对受影响的个体及其造成严重后果家庭，希望这项研究能够提供重要的知识，以帮助构成未来的潜在再生疗法。