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: 9752626
• 负责人: KAI G ZINN
• 金额: $ 33.5万
• 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/9752626
• 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; axonal 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 许多细胞表面蛋白（CSP）已确定为神经发育所必需的，但我们仍然缺乏 对这些CSP程序组装复合物介导的细胞电池相互作用的总体理解 神经回路。我们的长期目标是了解这些过程。许多年前，有人提出， “硬连线”神经元结构，例如鱼视网膜直肠系统和隔热视频叶，每个人 神经元被控制突触特异性的“识别标签”标记，并且这些标签表示 由特定的CSP称为“表面标签”。假设预测控制突触的表面标签 特异性应为：1）在每个大脑区域的神经元的小子集上表达，2）接收器识别 其表达也仅限于神经元子集，3）形成特定突触 连接，4）由相关基因家族编码。我们发现了一个交互的CSP网络 使用果蝇CSP的体外相互作用屏幕满足所有这些标准。在此屏幕中，我们 确定了21个2-gig结构域蛋白的亚家族DPRS，该蛋白有选择地结合了9个3-ig的另一个亚家族 域蛋白，倾角，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倾向于向表达DPR在体外结合的倾斜的神经元前突触前。这 本应用程序的目标是了解DPR-DIP互动如何调节竞争 神经营养信号的视觉系统神经元，并确定突触前的结合以及如何结合 DPR的突触后倾角伴侣控制突触的形成和功能。主要假设 此申请的基础是，DPR与其DIP合作伙伴的参与提供了信息 影响光叶中突触连接的细胞命运和模式。特别是，我们假设 确定细胞数需要DPR11及其伴侣DIP-γ之间的反式突触相互作用 和彩色电路中连接的规范。 DPR11由紫外线的亚型表示 光感受器，黄色（y）R7。 R7S的主要突触靶是无链氨酸神经元DM8。 DIP-γ是 由DM8（“ YDM8”）的子集选择性地表达，该子集选择性地用yr7s来表达。不成功的YDM8 神经R7死亡。 DIP-γ控制着他们争夺表达DPR11的YR7目标的能力，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 DPR11和DIP-γ之间DM8之间的相互作用。 AIM 2：通过DPR11-DIP-γ控制突触选择 互动。拟议的研究的预期结果将是获得新的见解 CSP之间的相互作用控制神经回路中的机制 系统。通过增加我们对人类健康的理解，这将对人类健康产生重大的积极影响 涉及发育和疾病的保守机制。