Eph-Ephrin Bidirectional Signaling in Visual Development

视觉发育中的 Eph-Ephrin 双向信号传导

• 批准号: 7386598
• 负责人: MARK J HENKEMEYER
• 金额: $ 37.35万
• 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/7386598
• 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; EphA1 Receptor; 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; Numbers; 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; Thinking; 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; relating to nervous system; research study; superior colliculus Corpora quadrigemina; vision development

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.

该应用集中于视觉系统的开发。目的是帮助我们更好地理解 视网膜神经节细胞（RGC）纤维如何进入大脑，使眼睛与中枢神经系统硬连线， 对视觉很重要的神经连接先前在小鼠中的研究表明， 受体酪氨酸激酶及其膜锚定的肝配蛋白配体参与三种不同的 RGC靶向的方面：1）在视网膜内，因为RGC纤维漏斗状进入视柄以形成视神经， 2）视交叉处作为RGC纤维选择向对侧或同侧投射， 3）在上级丘内，RGC纤维地形图反映了 眼的腹/背轴转变为丘的内侧/外侧轴。Eph受体和Ephrin配体 Eph-Ephrin是独特的分子，因为当Eph-Ephrin在细胞-细胞接触位点接合时， 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）。的 由Eph-Ephrin相互作用转导的双向信号通常导致细胞骨架的改变 其导致排斥或粘附/吸引细胞迁移和引导事件。的确，这三个 上述RGC纤维中Eph-Ephrin信号传导的例子似乎引起排斥， （示例1和2）或吸引（示例3）事件。在这个应用中，我们计划在体内实验， 进一步剖析了双向信号控制发育神经元的分子机制， 视觉系统我们将在小鼠生殖系中创建和分析新的突变和转基因构建体 其被设计为选择性地干扰前向和反向信令的特定分量。我们 研究将进一步推进我们对Eph-Ephrin 双向信号控制对视觉重要的引导事件。因为视觉对于 视力丧失和失明对受影响的个人及其 家庭，希望这项研究将提供重要的知识，可能有助于形成基础， 未来潜在的再生疗法。