Deciphering the molecular mechanisms in photoreceptor wiring

破译感光器布线的分子机制

• 批准号: 10280111
• 负责人: Elizabeth Zuniga-Sanchez
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280111
• 关键词: Address; Adhesives; Axon; B-Lymphocytes; Binding; Bipolar Neuron; Blindness; Brain; CNTNAP1 gene; Cell Adhesion Molecules; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cone; Data; Defect; Degenerative Disorder; Dendrites; Development; Ectopic Expression; Electroporation; Family; Goals; Knowledge; Label; Lead; Light; Mediating; Molecular; NRCAM gene; Neural Cell Adhesion Molecule L1; Neuraxis; Neurons; Pathway interactions; Patients; Pattern; Photoreceptors; Process; Research; Retina; Retinal Cone; Retinal Diseases; Rod; Specific qualifier value; Specificity; Structure; Synapses; Techniques; Testing; Time; Transgenic Mice; Vertebrate Photoreceptors; Visual; Work; base; cell type; contactin; detector; developmental disease; experimental study; gain of function; genetic manipulation; horizontal cell; in vivo; nervous system disorder; neural circuit; neurofascin; postsynaptic; protein expression; response; retinal rods; rho; sight restoration; synaptogenesis; transmission process; visual information

Project Summary Proper transmission of visual information relies on photoreceptors forming appropriate synaptic connections during development. Nearly all retinal diseases that lead to blindness are caused by loss of photoreceptors connections. Thus, elucidating the molecular mechanisms that mediate proper photoreceptor connectivity may lead to better therapies to treat patients with retinal diseases. During development, photoreceptors first synapse selectively to horizontal cells, where the dendrites of horizontal cells synapse to cone photoreceptors and the axon connects to rod photoreceptors. Cones and rods then synapse to their respective bipolar target. Cones synapse to cone bipolars and rods to rod bipolars. The molecular mechanisms that guide selective wiring of the different photoreceptors to their distinct synaptic partners remains poorly understood. Our data shows the L1 cell adhesion molecule Neurofascin (Nfasc) is localized to the synaptic layer during development and expressed in rods, horizontal cells, and rod bipolars. Moreover, we find disruption of Nfasc results in rod synaptic defects and abnormal rod-driven visual responses. As Nfasc is known to mediate adhesive interactions between neurons, we propose Nfasc is a key molecule mediating selective connectivity of rods to horizontal cells and then to rod bipolars. In addition, we find other cell adhesion molecules that are known to work alongside Nfasc (i.e. Caspr, Cntn1, Nrcam), to be expressed in the complementary cone pathway. Thereby, we hypothesize that restricted expression of cell adhesion molecules mediates selective wiring of the different photoreceptors to their respective targets. To test our hypothesis, we will mouse transgenics, in vivo genetic manipulations, and single neuron labeling approaches to identify the key molecular interactions that guide photoreceptors to synapse selectively to different partners. The proposed research will elucidate the adhesive molecular interactions that instruct selective wiring of photoreceptors to horizontal cells (Aim 1) and to bipolar neurons (Aim 2). Through these experiments, we will uncover the molecular mechanisms involved in complex wiring of neural circuits during development. This knowledge will be necessary to develop new strategies to restore vision in those with retinal diseases.

项目概要 视觉信息的正确传输依赖于光感受器形成适当的突触连接 在开发过程中。几乎所有导致失明的视网膜疾病都是由光感受器丧失引起的 连接。因此，阐明介导适当光感受器连接的分子机制可能 导致更好的疗法来治疗视网膜疾病患者。在发育过程中，光感受器首先产生突触 选择性地作用于水平细胞，水平细胞的树突与视锥细胞突触， 轴突连接到视杆光感受器。然后视锥细胞和视杆细胞突触到各自的双极目标。视锥细胞 突触到视锥双极和视杆到视杆双极。指导选择性布线的分子机制 不同的光感受器与其不同的突触伙伴之间的关系仍然知之甚少。我们的数据显示 L1 细胞 粘附分子神经成束蛋白（Nfasc）在发育过程中定位于突触层并表达于 视杆细胞、水平细胞和双极视杆细胞。此外，我们发现 Nfasc 的破坏会导致杆突触缺陷和 异常的杆驱动视觉反应。由于 Nfasc 已知可介导神经元之间的粘附相互作用， 我们认为 Nfasc 是介导视杆细胞与水平细胞、然后与视杆细胞选择性连接的关键分子 双相情感障碍者。此外，我们还发现其他已知与 Nfasc 一起发挥作用的细胞粘附分子（即 Caspr、 Cntn1、Nrcam)，在互补锥通路中表达。因此，我们假设限制 细胞粘附分子的表达介导不同光感受器与其各自的选择性连接 目标。为了检验我们的假设，我们将小鼠转基因、体内遗传操作和单个神经元 标记方法来识别引导光感受器选择性突触的关键分子相互作用 给不同的伙伴。拟议的研究将阐明指导的粘合剂分子相互作用 光感受器与水平细胞（目标 1）和双极神经元（目标 2）的选择性连接。通过这些 实验中，我们将揭示神经回路复杂接线所涉及的分子机制 发展。这些知识对于制定恢复视网膜患者视力的新策略是必要的。 疾病。