Molecular Basis of Photoreceptor Wiring

项目总结 哺乳动物的视杆和视锥感光细胞是视觉所必需的。它们将光转化为电 反应，然后通过视网膜回路传播到大脑。电子产品的传输 光感受器产生的信号需要它们与下游的中间神经元建立突触连接， 双极细胞。已知光感受器和双极细胞之间的突触通讯缺陷 导致人类先天性静止性失明，这种情况的特征是光敏感度低和 经常与许多其他眼部疾病并存。我们的长期目标是阐明分子和 光感受器建立突触并传递信号的细胞机制，希望 更好地了解致盲情况并制定治疗策略。 两种类型的感光器，视杆和视锥，与不同类型的 双极细胞。这种突触特异性将视觉输入隔离开来，并在建立 我们视觉的基本特性，包括大动态范围的光敏感度和对比度 歧视。然而，负责选择性连接的分子机制 光感受器及其下游的双极神经元尚不清楚。我们发现了一种新的细胞黏附- 就像ELFN1分子一样，它专门存在于光感受器突触上。我们发现ELFN1形成一种 与双极细胞中主要神经递质受体mGluR6的跨突触相互作用。中断 ELFN1导致视杆突触的选择性丢失。我们假设ELFN1-mGluR6相互作用发挥关键作用 介导杆状感光细胞选择性突触连接和引导光传播的作用 信号通过视网膜电路。 这一假设将通过追求三个相辅相成的具体目标来检验，这三个目标将(I)使用 基因敲除小鼠模型和基因拯救实验以确定ELFN1功能的细胞机制 在杆状光感受器和On-RBC之间形成突触的过程中，(Ii)研究ELFN1在 引导传播光信号穿过视网膜电路，以及(Iii)检查分子机制，通过这些机制 ELFN1使其具有突触生成作用。为实现这些目标而提出的战略将需要协同增效 生化、分子生物学、电生理和生理学方法的组合，每种方法 利用一系列强大的试剂和动物模型的存在。

PROJECT SUMMARY Mammalian rod and cone photoreceptors are indispensible for vision. They convert light into electrical response, which is then propagated across the retina circuit and into the brain. Transmission of the electrical signal generated by the photoreceptors requires their synaptic connectivity with the downstream interneurons, the bipolar cells. Deficits in synaptic communication between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, a condition characterized by poor light sensitivity and frequent co-morbidity with many other ocular conditions. Our long-term goal is to elucidate molecular and cellular mechanisms by which photoreceptors establish synapses and transmit their signals with the hope to better understand blinding conditions and devising strategies for their treatment. Two types of the photoreceptors, rods and cones, form distinct connections with different types of the bipolar cells. This synaptic specificity segregates visual inputs and plays an essential role in setting up the fundamental properties of our vision, including a wide dynamic range of light sensitivity and contrast discrimination. However, the molecular mechanisms responsible for selective connectivity between photoreceptors and their downstream bipolar neurons are unknown. We have identified a new cell adhesion- like molecule ELFN1 that specifically present at the photoreceptors synapses. We found that ELFN1 forms a trans-synaptic interaction with the principal neurotransmitter receptor in bipolar cells, mGluR6. Disruption of ELFN1 results in selective loss of rod synapses. We hypothesize that ELFN1-mGluR6 interaction play key roles in mediating selective synaptic connectivity of rod photoreceptors and direct the propagation of light signal across retina circuit. This hypothesis will be tested by pursuing three complementary Specific Aims that will (i) use knockout mouse models, and genetic rescue experiments to determine cellular mechanisms of ELFN1 function in the formation of synapse between rod photoreceptors and ON-RBC, (ii) investigate the role of ELFN1 in directing the propagation light signal across retina circuitry, and (iii) examine molecular mechanisms by which ELFN1 enables its synaptogenic effects. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models.