AXON GUIDANCE MECHANISMS IN DROSOPHILA

描述(摘自申请者的摘要)：在对称的神经系统中 在中线，大量神经元从一侧投射轴突。 对另一个人。尽管已经发现有几种分子控制着 直到最近，无论轴突是否穿过中线，它都保持在 不知道这些轴突是如何选择合适的路径的 穿越，这是一个对神经系统功能至关重要的选择。在 果蝇胚胎，轴突穿过中线，在两个不同的束之一， 前连合或后连合(分别为前连合或后连合)。脱轨(DRL) 受体酪氨酸激酶在ALL的生长锥体和轴突上表达 横穿AC中线的神经元，起着引导受体的作用。 存在于PC中的一种排斥配体。这个项目的目标是了解 DRL引导机制如何正确地引导轴突穿过 中线。 信号传递所需的DRL受体区域将通过 检测一系列缺失和特定氨基酸替换。一位批评者 DRL功能的特点是其对生长锥体和轴突的下调 他们离开空调。利用体内试验，其所需的DRL区域 下调监管将被定义。DRL的配体，以及 DRL受体在生长发育中的信号转导途径 将使用遗传和生化策略进行鉴定。确实有 可能是与DRL协同作用的其他导向受体和配体 当轴突穿过中线时，对它们进行排序，并且是这种 分子是Drl2，DRL家族的另一个成员，显然是在PC中表达的 神经元。Drl2在连合选择中的作用将通过错误表达来定义 研究并通过在基因中产生突变。最后，新基因 控制连合的选择将被隔离在基因筛查中。给定 脊椎动物DRL同源物的存在，加上 其他中线交叉组件，有可能像DRL一样引导 这种机制将在所有复杂的神经系统中运行。

DESCRIPTION (From the Applicant's Abstract): In nervous systems with symmetry about the midline, a substantial number of neurons project axons from one side to the other. Although several molecules have been identified that control whether or not an axon crosses the midline, until recently it has remained unknown how these same axons manage to choose the appropriate pathway in which to cross, a choice that is critical for nervous system function. In the Drosophila embryo, axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (Ac or PC, respectively). The Derailed (Drl) receptor tyrosine kinase is expressed on the growth cones and axons of all neurons that traverse the midline in the AC and acts as a guidance receptor for a repellent ligand present in the PC. The goal of this project is to understand how the Drl guidance mechanism functions to properly route axons across the midline. Regions of the Drl receptor required for signaling will be identified by testing a series of deletions and specific amino acid substitutions. A critical feature of Drl function is its down-regulation in growth cones and axons after they leave the AC. Using an in vivo assay, the regions of Drl required for its down-regulation will be defined. Drl's ligand, as well as components of the signal transduction pathway through which the Drl receptor acts in the growth cone, will be identified using genetic and biochemical strategies. There are likely to be other guidance receptors and ligands acting in concert with Drl to sort axons as they traverse the midline, and a prime candidate for such a molecule is Drl2, another member of the Drl family apparently expressed in PC neurons. The role of Drl2 in commissure choice will be defined by misexpression studies and by generating mutations in the gene. Finally, novel genes controlling commissure choice will be isolated in a genetic screen. Given the existence of vertebrate Drl homologs, plus the evolutionary conservation of other midline crossing components, it is possible that a Drl-like guidance mechanism will be operating in all complex nervous systems.