Deciphering the molecular mechanisms in photoreceptor wiring

项目摘要 视觉信息的正确传递依赖于光感受器形成适当的突触连接 在发展过程中。几乎所有导致失明的视网膜疾病都是由光感受器的丧失引起的 连接.因此，阐明调节感光细胞连接的分子机制， 导致更好的治疗视网膜疾病的方法。在发育过程中，光感受器首先 选择性地对水平细胞，其中水平细胞的树突与视锥光感受器突触， 轴突与视杆细胞相连然后视锥细胞和视杆细胞与它们各自的双极靶细胞形成突触。锥 突触到锥双极和杆到杆双极。引导细胞选择性连接的分子机制 不同的光感受器与其不同的突触伴侣之间的相互作用仍然知之甚少。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，并在神经细胞中表达。 杆状细胞、水平细胞和杆状双极细胞。此外，我们发现Nfasc的破坏导致视杆细胞突触缺陷， 异常的视杆驱动视觉反应由于已知Nfasc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 两极此外，我们发现了已知与Nfasc一起工作的其他细胞粘附分子（即Caspr， Cntn1，Nrcam），以在互补锥途径中表达。因此，我们假设， 细胞粘附分子的表达介导不同光感受器与它们各自的细胞粘附分子的选择性连接。 目标的为了验证我们的假设，我们将在小鼠转基因，体内遗传操作和单神经元， 标记方法，以确定引导光感受器选择性突触的关键分子相互作用 不同的合作伙伴。这项研究将阐明粘附分子间的相互作用， 光感受器与水平细胞（Aim 1）和双极神经元（Aim 2）的选择性连接。通过这些 实验中，我们将揭示参与神经回路复杂布线的分子机制， 发展这些知识将是必要的，以制定新的战略，以恢复视力，在那些视网膜病变 疾病

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.