AXON GUIDANCE MECHANISMS IN DROSOPHILA

描述（来自申请人的摘要）：在具有对称性的神经系统中 在中线附近，大量的神经元从一侧投射轴突 另一个。尽管已经鉴定出几种控制 无论轴突是否穿过中线，直到最近， 我们不知道这些轴突是如何选择合适的通路， 交叉，一个对神经系统功能至关重要的选择。在 在果蝇胚胎中，轴突在两条不同的神经束中的一条穿过中线， 前连合或后连合（分别为Ac或PC）。出轨（Drl） 受体酪氨酸激酶表达在所有的生长锥和轴突上， 在AC中穿过中线的神经元，并作为引导受体， 存在于PC中的排斥性配体。这个项目的目标是了解 DRL引导机制如何发挥作用，以正确地将轴突穿过 中线 信号传导所需的Drl受体的区域将通过以下鉴定： 测试一系列的缺失和特定的氨基酸替换。一个关键 Drl功能的特征是其在生长锥和轴突中的下调， 他们离开了AC。使用体内测定法，测定了其表达所需的Drl区域。 将定义下调。DRL的配体，以及 Drl受体在生长中起作用的信号转导途径 锥，将确定使用遗传和生化策略。有 可能是与Drl协同作用的其他引导受体和配体， 分类轴突，因为他们穿越中线，和这样的一个主要候选人， 分子是Drl2，Drl家族的另一个成员，显然在PC中表达 神经元Drl2在连合选择中的作用将通过错误表达来定义。 研究和在基因中产生突变。最后，新基因 控制合缝选择将在遗传筛选中被分离。鉴于 脊椎动物Drl同源物的存在，加上 其他中线交叉组件，有可能是一个类似DRL的指导 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.