Cell Surface Protein Interactions Controlling Photoreceptor Synaptic Targeting and Amacrine Cell Fate in the Drosophila Visual System

控制果蝇视觉系统中光感受器突触靶向和无长突细胞命运的细胞表面蛋白相互作用

• 批准号: 10176503
• 负责人: KAI G ZINN
• 金额: $ 32.5万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176503
• 关键词: Amacrine Cells; Amphibia; Area; Binding; Birth; Brain; Cell Communication; Cell Count; Cell Death; Cell Surface Proteins; Cells; Collaborations; Color Visions; Complex; Development; Disease; Drosophila genus; Family; Fishes; Genes; Goals; Health; Human; Immunoglobulins; In Vitro; Individual; Insecta; Label; Lead; Mediating; Neurons; Neurophysiology - biologic function; Opsin; Optic Lobe; Outcome; Pathway interactions; Pattern; Photoreceptors; Process; Property; Proteins; Research; Research Project Grants; Retina; Signal Transduction; Specificity; Stereotyping; Structure; Surface; Synapses; System; Tertiary Protein Structure; Time; Ursidae Family; Visual; Visual system structure; Work; axon guidance; cell determination; extracellular; insight; nerve supply; nervous system development; neural circuit; neurodevelopment; neuronal circuitry; postsynaptic; presynaptic; programs; receptor; relating to nervous system; retinotectal; selective expression; synaptic function; synaptogenesis

Project Summary/Abstract Many cell surface proteins (CSPs) essential for neural development have been identified, but we still lack an overall understanding of how cell-cell interactions mediated by these CSPs program assembly of complex neural circuits. Our long-term goal is to understand these processes. Many years ago, it was proposed that, in “hard-wired” neural structures such as the fish retinotectal system and the insect optic lobe, each individual neuron is labeled by “identification tags” that control synaptic specificity, and that these tags are represented by specific CSPs called “surface labels”. The hypotheses predicted that surface labels that control synaptic specificity should be: 1) expressed on small subsets of neurons in each brain area, 2) recognized by receptors whose expression is also restricted to neuronal subsets, 3) required for formation of specific synaptic connections, 4) encoded by families of related genes. We discovered a network of interacting CSPs that satisfies all of these criteria, using an in vitro interaction screen of Drosophila CSPs. In this screen, we identified a subfamily of 21 2-Ig domain proteins, the Dprs, that selectively bind to another subfamily of 9 3-Ig domain proteins, the DIPs, forming a network called the Dpr-ome. In the visual system, neurons expressing a particular Dpr tend to be presynaptic to neurons expressing a DIP to which that Dpr binds in vitro. The objectives of the present application are to understand how Dpr-DIP interactions regulate competition among visual system neurons for neurotrophic signals, and to determine whether and how binding of a presynaptic Dpr to its postsynaptic DIP partner controls formation and function of synapses. The primary hypothesis underlying this application is that engagement of Dprs with their DIP partners provides information that influences cell fates and patterns of synaptic connections in the optic lobe. In particular, we hypothesize that trans-synaptic interactions between Dpr11 and its partner DIP-γ are required for determination of cell numbers and specification of connections in the color vision circuit. Dpr11 is expressed by a subtype of UV photoreceptors, the yellow (y) R7s. The primary synaptic target for R7s is the amacrine neuron Dm8. DIP-γ is expressed by a subset of Dm8s (“yDm8s”) that selectively arborizes with yR7s. yDm8s that do not successfully innervate R7s die. DIP-γ controls their ability to compete for Dpr11-expressing yR7 targets and thereby regulates cell death. We plan to attain our objectives through two specific aims. Aim 1: Control of competitive interactions among Dm8s by Dpr11 and DIP-γ. Aim 2: Control of synaptic selection by Dpr11-DIP-γ interactions. The expected outcome of the proposed research will be the acquisition of new insights into the mechanisms by which interactions among CSPs control the assembly of neural circuits in the developing visual system. This will have a significant positive impact for human health by increasing our understanding of conserved mechanisms involved in development and disease.

项目总结/摘要 许多神经发育所必需的细胞表面蛋白（CSP）已经被鉴定出来，但我们仍然缺乏一个完整的细胞表面蛋白。 全面了解这些CSP如何介导细胞间相互作用， 神经回路我们的长期目标是了解这些过程。多年前，有人提出，在 “硬连线”神经结构，如鱼类视网膜顶盖系统和昆虫视叶，每个个体 神经元由控制突触特异性的“识别标签”标记，并且这些标签被表示为 被称为“表面标签”的特定CSP标记。这些假说预测，控制突触的表面标记 特异性应该是：1）在每个脑区的小神经元子集上表达，2）被受体识别 其表达也仅限于神经元亚群，3）形成特异性突触所需的 连接，4）由相关基因家族编码。我们发现了一个相互作用的CSP网络， 满足所有这些标准，使用果蝇CSP的体外相互作用筛选。在这个屏幕上，我们 鉴定了21个2-IG结构域蛋白质的亚家族，DIFF 1，其选择性地结合另一个3-IG亚家族 结构域蛋白，DIP，形成一个称为Dpr-ome的网络。在视觉系统中，神经元表达 特定的Dpr倾向于与表达Dpr在体外结合的DIP的神经元突触前。的 本申请的目的是理解Dpr-DIP相互作用如何调节 视觉系统神经元的神经营养信号，并确定是否以及如何结合突触前 Dpr与其突触后DIP配偶体控制突触的形成和功能。主要假设 这一应用的基础是，DALF与其DIP合作伙伴的合作提供了信息， 影响视叶中细胞的命运和突触连接的模式。特别是，我们假设， Dpr 11和它的伙伴DIP-γ之间的跨突触相互作用是确定细胞数量所必需的 以及色觉电路中的连接规范。Dpr 11由UV的一个亚型表达， 光感受器，黄色（y）R7。R7s的主要突触靶点是无长突神经元Dm 8。DIP-γ是 由选择性地与yR 7分支的Dm 8 s的子集（“yDm 8 s”）表示。yDm 8不成功 受神经支配R7死亡。DIP-γ控制它们竞争表达Dpr 11的yR 7靶标的能力，从而 调节细胞死亡。我们计划通过两个具体目标实现我们的目标。目标1：控制竞争 Dpr 11和DIP-γ与Dm 8 s之间的相互作用。目的2：通过Dpr 11-DIP-γ控制突触选择 交互.拟议研究的预期成果将是获得对 CSPs之间的相互作用控制发育中视觉神经回路的组装的机制 系统这将对人类健康产生重大的积极影响， 参与发育和疾病的保守机制。