Characterizing Novel Regulations of Dendritic Tiling in C. elegans

项目摘要 神经元依靠树突从其特定的感受野获取感觉和突触输入。 在自闭症谱系障碍（ASD）和自闭症等疾病中异常树突状形态的发现 精神分裂症突出了了解复杂的树突状乔木是如何发展的重要性， 树立政治意识在发育过程中，树突状生长的目标之一是不冗余地覆盖一个 感受野，这需要避免来自同一神经元的其他树突（自我回避）， 其他的（tilling）。平铺在感觉神经突的组织中是明显的，如C。elegans 机械感觉神经元、果蝇树突状分支（DA）神经元和脊椎动物视网膜神经节细胞。 虽然平铺是许多神经系统的保守特性，但它的分子机制 成立尚不清楚。该项目的目标是揭示遗传和分子机制， 树突平铺使用多树突FLP和PVD机械感觉神经元的C。优雅的模特的 FLP的树枝状心轴覆盖蜗杆的头部，而PVD的心轴覆盖蜗杆的主体。虽然以前的 研究已经确定了细胞自主和细胞非自主的自我回避线索， PVD树突，FLP和PVD建立不同的非重叠感受野的机制 仍然未知。从一个试点的遗传筛查，我已经确定unc-33作为一个基因所需的 FLP和PVD感受野尺寸的规格。Unc-33是Collapsin Response Mediator成员 CRMP是CRMP家族的成员，已知其通过微管的组织化来调节轴突发育。 尽管unc-33在轴突生长中的作用已被很好地描述，但其在树突状铺瓦中的作用尚不清楚。上 本项目的目的，我将使用延时成像和细胞消融实验来表征正常的 FLP和PVD神经元之间平铺的发展。在本项目的第二个目标中，我将使用遗传和 分子技术来确定unc-33在调节FLP和PVD镶嵌中的作用机制。在 本项目的第三个目标是，我将使用一种组合的候选和正向遗传方法来鉴定新的调节因子 FLP和PVD神经元之间的平铺。本项目的结果将建立FLP和PVD作为一种新的模式 用于研究树突状镶嵌，并确定调节这一过程的新途径。了解基本 枝晶形态的发展机制将为理解 这些机制在神经发育障碍中是如何改变的。

PROJECT SUMMARY Neurons rely on dendrites for the acquisition of sensory and synaptic input from their particular receptive fields. Findings of aberrant dendritic morphology in disorders such as autism spectrum disorder (ASD) and schizophrenia highlight the importance of understanding how complex dendritic arbors are developed and maintained. During development, one of the goals of dendritic outgrowth is non-redundant coverage of a receptive field, which requires the avoidance of other dendrites both from the same neuron (self-avoidance) and from others (tiling). Tiling is evident in the organization of sensory neurites, such as those of C. elegans mechanosensory neurons, drosophila dendritic arborization (da) neurons, and vertebrate retinal ganglion cells. While tiling is a conserved property of many nervous systems, the molecular mechanisms by which it is established remain unclear. The goal of this project is to uncover the genetic and molecular mechanisms of dendritic tiling using the multi-dendritic FLP and PVD mechanosensory neurons of C. elegans as a model. The dendritic arbor of FLP covers the head of the worm while the arbor of PVD covers the body. While previous studies have identified both cell autonomous and cell non-autonomous cues for self-avoidance in outgrowing PVD dendrites, the mechanisms by which FLP and PVD establish distinct non-overlapping receptive fields remains unknown. From a pilot forward genetic screen, I have identified unc-33 as a gene required for the specification of FLP and PVD receptive field size. Unc-33 is a member of the Collapsin Response Mediator Protein (CRMP) family and is known to regulate axon development through the organization of microtubules. While the role of unc-33 in axon outgrowth is well-characterized, its role in dendritic tiling is unclear. In the first Aim of this project, I will use time-lapse imaging and cell ablation experiments to characterize the normal development of tiling between FLP and PVD neurons. In the second Aim of this project, I will use genetic and molecular techniques to determine the mechanism of action of unc-33 in regulating FLP and PVD tiling. In the third Aim of this project, I will use a combined candidate and forward genetic approach to identify novel regulators of tiling between FLP and PVD neurons. The results from this project will establish FLP and PVD as a new model for the study of dendritic tiling and identify novel pathways regulating this process. Understanding the basic mechanisms for the development for dendritic morphology will provide a foundation from which to understand how these mechanisms are altered in neurodevelopmental disorders.