Deciphering the molecular mechanisms in photoreceptor wiring

破译感光器布线的分子机制

• 批准号: 10723128
• 负责人: Elizabeth Zuniga-Sanchez
• 金额: $ 7.22万
• 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/10723128
• 关键词: Address; Adhesives; Axon; B-Lymphocytes; Binding; Bipolar Neuron; Blindness; Brain; CNTNAP1 gene; Cell Adhesion Molecules; Central Nervous System; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cone; Data; Defect; Degenerative Disorder; Dendrites; Development; Ectopic Expression; Electroporation; Family; Goals; Knowledge; Label; Light; Mediating; Molecular; NRCAM gene; Neural Cell Adhesion Molecule L1; Neurons; Pathway interactions; Patients; Pattern; Photoreceptors; Process; Research; Retina; Retinal Cone; Retinal Diseases; Rod; Specific qualifier value; Specificity; Synapses; Techniques; Testing; Transgenic Mice; Vertebrate Photoreceptors; Visual; Work; cell type; contactin; detector; developmental disease; experimental study; gain of function; genetic manipulation; horizontal cell; in vivo; loss of function; nervous system disorder; neural circuit; neurofascin; organizational structure; 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.

项目摘要 正确传输视觉信息取决于形成适当突触连接的光感受器 在开发过程中。几乎所有导致失明的视网膜疾病都是由于失去感受器引起的 连接。因此，阐明介导适当光感受器连接性的分子机制可能 导致更好的治疗视网膜疾病患者的疗法。在开发过程中，光感受器首先突触 有选择地到水平细胞，其中水平细胞的树突突触到锥形感受器和 轴突连接到杆感光体。然后，锥和杆突触到各自的双极靶。锥 突触到锥双皮拉棒和杆的杆两杆。指导选择性接线的分子机制 对其独特的突触伙伴的不同感光体仍然对其进行了鲜为人知的理解。我们的数据显示了L1单元 粘附分子神经胶质素（NFASC）在发育过程中定位于突触层，并在 杆，水平细胞和杆双曲线。此外，我们发现NFASC的破坏导致杆突触缺陷和 异常的杆驱动视觉响应。由于已知NFASC介导神经元之间的粘合剂相互作用，所以 我们提出的NFASC是介导杆与水平细胞的选择性连通性，然后介导杆的关键分子 两双。此外，我们发现其他已知与NFASC一起工作的细胞粘附分子（即Caspr， cntn1，nrcam），在互补锥途径中表达。因此，我们假设该受限制 细胞粘附分子的表达介导不同感光体的选择性接线 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 标记方法以识别指导光感受器选择性地突触的关键分子相互作用 给不同的合作伙伴。拟议的研究将阐明指示的粘合分子相互作用 光感受器的选择性接线至水平细胞（AIM 1）和双极神经元（AIM 2）。通过这些 实验，我们将发现与神经回路复杂布线有关的分子机制 发展。这些知识将是必要的，以制定新的策略来恢复视网膜的人 疾病。