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: 10405482
• 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/10405482
• 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.

项目摘要/摘要 许多对神经发育至关重要的细胞表面蛋白(CSP)已经被鉴定出来，但我们仍然缺乏 全面了解这些CSP如何介导细胞-细胞相互作用程序组装复合体 神经回路。我们的长期目标是了解这些过程。许多年前，有人提议，在 “硬连线”的神经结构，如鱼类视网膜顶盖系统和昆虫视叶，每一个个体 神经元由控制突触专一性的“识别标签”来标记，并且这些标签被表示 被称为“表面标签”的特定CSP。这些假说预测控制突触的表面标记 特异性应该是：1)在每个脑区的神经元小亚群上表达，2)由受体识别 它的表达也限于神经元亚群，3)形成特定突触所必需的 联系，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 使用果蝇CSPs的体外相互作用筛选，满足所有这些标准。在此屏幕中，我们 鉴定了21个2-Ig结构域蛋白的亚家族dprs，它选择性地与另一个9 3-Ig亚家族结合 结构域蛋白，DIP，形成一个称为DPR-OME的网络。在视觉系统中，表达一种 在体外，特定的DPR倾向于与表达DIP的神经元发生突触前反应。这个 本申请的目的是了解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对其突触后DIP伙伴控制突触的形成和功能。主要假设 此应用程序的基础是DPR与其DIP合作伙伴的接洽提供了以下信息 影响细胞命运和视叶突触连接的模式。特别是，我们假设 Dpr11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 以及彩色视觉电路中的连接的规范。Dpr11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Dm8。DIP-γ是 由选择性地与yR7分枝的Dm8(“yDm8”)的子集表示。不成功的yDm8 会导致R7死亡。DIP-γ控制他们竞争表达Dpr11的yr7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来实现我们的目标。目标1：控制竞争性 DPr11和DIP-γ研究Dm8之间的相互作用目的2：Dpr11-DIP-γ对突触选择的调控 互动。拟议研究的预期结果将是获得对 CSP之间的相互作用控制发育视觉中神经回路组装的机制 系统。这将对人类健康产生重大的积极影响，因为它增加了我们对 与发育和疾病有关的保守机制。

项目成果

Neural mechanism of spatio-chromatic opponency in the Drosophila amacrine neurons.

果蝇无长突神经元空间色彩对抗的神经机制。

• DOI: 10.1016/j.cub.2021.04.068
• 发表时间: 2021
• 期刊: Current biology : CB
• 作者: Li,Yan;Chen,Pei-Ju;Lin,Tzu-Yang;Ting,Chun-Yuan;Muthuirulan,Pushpanathan;Pursley,Randall;Ilić,Marko;Pirih,Primož;Drews,MichaelS;Menon,KaushikiP;Zinn,KaiG;Pohida,Thomas;Borst,Alexander;Lee,Chi-Hon
• 通讯作者: Lee,Chi-Hon