Dendritic patterning by interacting extrinsic cues

描述(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。生长中的树枝晶必须同时与其底物相互作用，对引导其到达适当区域的吸引信号做出反应，并对来自其他树枝晶的排斥信号做出反应，以确保对该区域的无冗余覆盖。调控树突引导和区域覆盖的分子机制，以及这些机制之间的相互作用，是复杂的，还没有被很好地理解。在同一细胞的树突(姐妹树突)之间运行的排斥线索会引起自我回避现象。Dscam是一种高度选择性剪接的免疫球蛋白超家族分子，已被证明调节果蝇感觉神经元树突的自我回避。DSCAM分子多样性似乎在树突表面提供了一种自我和非自我区分的机制，使得只有可能是唯一表达相同DSCAM亚型的分支的姐妹树枝才能识别和排斥彼此。DSCAM实施的强大的自我识别和回避可能需要额外的机制，将树枝限制在相同的生长平面上。这项提议的初步目标将是测试树枝和它们的底物之间的相互作用在加强姐妹分支之间发生的强烈排斥作用方面的作用和调节。在其他情况下，树突可能被迫整合两个重合但相互冲突的细胞外信号。这种对抗性似乎是树突自我回避和吸引引导之间的关系的特征。当某些感觉神经元的自我回避能力受损时，它们的树枝聚集在特定的、解剖学上定义的焦点上。对这种现象的一种解释是，吸引人的引导线索从这些焦点释放出来，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能共同作用，以确保树突领域的适当发展。作为这个项目的第二个目标，我们描述了作用于感觉神经元树突模式的指导线索的来源和分子性质。在这个系统中可以检测树突靶向和靶向缺陷的分辨率将被用于第三个目标，以识别调节树突引导的新基因。这些研究将阐明树突如何对其环境中复杂的细胞外线索做出反应，以确保神经电路的正确组装。树突如何在神经系统中获得合适的形态和靶点尚不清楚，然而，树突形态的异常与多种神经疾病有关，包括癫痫、智力低下和精神分裂症。我们采用遗传学的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有望对理解树突发育和神经回路形成的正常和中断状态具有重要意义。

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.