Dendritic patterning by interacting extrinsic cues

描述（由申请人提供）：在神经回路的形成过程中，神经元的树突必须在分子复杂的细胞外环境中找到自己的路。生长的树突必须同时与其基底相互作用，响应将其引导到其适当区域的吸引信号，并响应来自其他树突的排斥信号，以确保该区域的非冗余覆盖。调节树突引导和领土覆盖的分子机制，以及这些机制之间的相互作用，是复杂的，并没有得到很好的理解。在同一细胞的树突（姐妹树突）之间运作的排斥性线索引起了自我回避的现象。Dscam是一种高度选择性剪接的免疫球蛋白超家族分子，已被证明可调节果蝇感觉神经元树突中的自我回避。Dscam分子多样性似乎提供了在树突表面自我与非自我区分的机制，使得只有姐妹树突（其可能是表达相同Dscam同种型的唯一分支）彼此识别和排斥。强大的自我识别和避免Dscam可能需要额外的机制，限制枝晶乔木相同的平面生长。这个建议的最初目的是测试树突和它们的基底之间的相互作用的作用和调节，以加强姐妹分支之间发生的强大的排斥相互作用。在其他情况下，树突可能被迫整合两个一致的，但冲突的细胞外信号。这种拮抗作用似乎表征树突自我回避和有吸引力的指导之间的关系。当某些感觉神经元的自我回避功能受损时，它们的树突会聚集在特定的、解剖学定义的病灶处。对这种现象的一种解释是，有吸引力的引导线索从这些焦点中释放出来，而自我回避通常起到对抗这些线索的作用。通过这种相互作用，自我回避和树突靶向可以共同作用以确保树突场的适当发展。作为这个项目的第二个目标，我们的特点的来源和分子性质的指导线索的模式感觉神经元树突。在该系统中可以测定树突靶向和靶向缺陷的分辨率将用于第三个目的，以鉴定调节树突指导的新基因。这些研究将阐明树突是如何对环境中复杂的细胞外信号做出反应以确保神经回路的正确组装的。树突是如何在神经系统中获得其正确的形态和靶点的还知之甚少，然而，异常的树突形态与多种神经系统疾病有关，包括癫痫、精神发育迟滞和精神分裂症。我们采取遗传学方法来阐明控制树突发育的机制。在这项工作中获得的基本见解，预计将有意义的理解正常和中断状态的树突发育和神经回路的形成。

DESCRIPTION (provided by applicant): During the formation of neural circuits, a neuron's dendritic arbor must find its way within a molecularly complex extracellular milieu. A growing dendrite must simultaneously interact with its substrate, respond to attractive signals that guide it to its proper territory, and respond to repulsive signals from other dendrites to ensure non-redundant coverage of that territory. The molecular mechanisms regulating dendrite guidance and territory coverage, and the interactions between these mechanisms, are complex and not well understood. Repulsive cues that operate between dendrites of the same cell (sister dendrites) give rise to the phenomenon of self- avoidance. Dscam, a highly alternatively spliced immunoglobulin superfamily molecule, has been shown to regulate self-avoidance in Drosophila sensory neuron dendrites. Dscam molecular diversity appears to provide a mechanism of self- vs. non-self discrimination at the dendrite surface, such that only sister dendrites, which are likely the only branches that express the same Dscam isoforms, recognize and repel each other. The robust self-recognition and avoidance enforced by Dscam likely requires additional mechanisms that restrict dendrite arbors to the same plane of growth. An initial aim of this proposal will be to test the role and regulation of interactions between dendrites and their substrate in reinforcing the robust repulsive interactions that occur between sister branches. In other contexts, dendrites might be forced to integrate two coincident, but conflicting, extracellular signals. Such antagonism appears to characterize the relationship between dendrite self-avoidance and attractive guidance. When self-avoidance is impaired in certain sensory neurons, their dendritic arbors aggregate at specific, anatomically defined foci. One explanation for this phenomenon is that attractive guidance cues are released from these foci, and that self-avoidance normally functions to antagonize these cues. Through this interaction, self-avoidance and dendrite targeting may act together to ensure proper development of dendritic fields. As a second aim of this project, we characterize the sources and molecular nature of guidance cues acting to pattern sensory neuron dendrites. The resolution with which dendrite targeting and targeting defects can be assayed in this system will be used in the third aim to identify new genes that regulate dendrite guidance. These studies will elucidate how dendrites respond to the complex extracellular cues in their environment to ensure proper assembly of neural circuits.How dendrites acquire their proper morphologies and targets in the nervous system is poorly understood, however, aberrant dendrite morphology is associated with diverse neurological disorders, including epilepsy, mental retardation, and schizophrenia. We take genetic approaches to elucidate mechanisms that control dendrite development. Basic insights gained during this work are expected to be of significance for understanding normal and disrupted states of dendrite development and neural circuit formation.