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。 关系。因此，阐明调节适当的光感受器连接的分子机制可能 导致更好的治疗视网膜疾病的方法。在发育过程中，光感受器首先会突触 选择性地到达水平细胞，在那里水平细胞的树突突触到锥形光感受器和 轴突与杆状感光器相连。然后，锥体和视杆突触到它们各自的两极目标。圆锥体 突触连接到锥形双极，杆状突触连接到杆状双极。引导细胞选择性连接的分子机制 不同的光感受器对其不同的突触伙伴仍然知之甚少。我们的数据显示L1细胞 黏附分子神经筋膜蛋白(NFasc)在发育过程中定位于突触层，并在 杆、水平单元和杆双极。此外，我们发现，破坏NFasc会导致视杆突触缺陷和 杆状驱动的异常视觉反应。众所周知，NFasc可以调节神经元之间的粘连相互作用， 我们认为NFasc是一个关键分子，它介导杆状细胞选择性地连接到水平细胞，然后再连接到杆状细胞。 双极星。此外，我们还发现了其他已知与NFasc(即CASPR， Cntn1，NrCAM)，在互补锥体途径中表达。因此，我们假设受限制的 细胞黏附分子的表达介导不同的光感受器与其各自的选择性连接 目标。为了验证我们的假设，我们将进行小鼠转基因、体内遗传操作和单个神经元 识别引导光感受器选择性突触的关键分子相互作用的标记方法 给不同的合作伙伴。这项拟议的研究将阐明粘合分子之间的相互作用 光感受器选择性连接水平细胞(目标1)和双极神经元(目标2)。通过这些 实验中，我们将揭示神经回路复杂连接的分子机制 发展。这一知识对于开发恢复视网膜患者视力的新策略是必要的。 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.