Development of sensory axon pathways in zebrafish

描述（由申请人提供）：在神经发育过程中，轴突延伸通过含有影响其生长和方向的大量引导分子的环境。关于轴突生长锥在复杂的体内环境中是如何被引导的，仍然知之甚少。我们感兴趣的是特定的轴突引导问题，即来自一个神经元的两个轴突分支如何沿着沿着不同的路径被引导到不同的目标。神经元经常将轴突投射到多个目标，并且几乎不知道它们的轴突分支是如何被差异引导的。我们使用斑马鱼脊髓感觉神经元作为模型，因为它们是具有良好表征的简单轴突轨迹的简单神经元类型。这些神经元延伸两个主要的轴突分支，中央和外周轴突，它们显示出非常不同的行为和轨迹。这个项目的目标是研究这些轴突沿着其特定通路的引导机制，并阐明引导它们的分子线索的功能。斑马鱼胚胎是一个很好的系统，研究轴突导向机制在体内，因为我们可以很容易地操纵导向分子和图像效果的轴突生长锥的动态行为在完整的活胚胎。我们的具体目标是1）使用活体成像来表征外周轴突最初在与中央轴突正交的方向上延伸并离开脊髓时的行为，研究已知对外周轴突延伸重要的两种分子的作用，并研究差异轴突引导的细胞内信号事件; 2）鉴定和分析参与感觉轴突引导的新分子的功能;和3）表征和克隆来自具有缺陷感觉轴突通路的突变体的突变基因。总的来说，我们的研究旨在了解促进和抑制轴突生长的过程，以及神经系统复杂树枝状结构的模式。了解这些机制对于理解神经发育疾病和损伤后轴突再生的条件是重要的。 项目叙述：了解促进和抑制神经元轴突生长的复杂过程，以及引导轴突到达正确靶点的分子的功能，对于理解神经发育疾病至关重要。此外，这些机制的知识将有助于了解损伤后轴突再生的条件。

DESCRIPTION (provided by applicant): During neural development, axons extend through an environment containing a multitude of guidance molecules that influence their growth and direction. There is still relatively little known about how axonal growth cones are guided in the complex in vivo environment. We are interested in the particular axon guidance question of how two axon branches from one neuron are guided along separate pathways to distinct targets. Neurons often project axons to more than one target, and virtually nothing is known about how their axon branches are differentially guided. We use zebrafish spinal sensory neurons as a model because they are a simple neuronal type with well- characterized simple axon trajectories. These neurons extend two main axon branches, the central and peripheral axons, which display very different behaviors and trajectories. The goal of this project is to investigate mechanisms of guidance of these axons along their particular pathways and to elucidate the function of the molecular cues that guide them. The zebrafish embryo is an excellent system to investigate axon guidance mechanism in vivo because we can readily manipulate guidance molecules and image effects on dynamic behavior of axonal growth cones in the intact living embryo. Our specific aims are 1) to use live imaging in vivo to characterize the behavior of the peripheral axon as it initially extends in an orthogonal direction to the central axon and exits the spinal cord, investigate the roles of two molecules known to be important for peripheral axon extension, and investigate the intracellular signaling events underlying the differential axon guidance; 2) to identify and analyze the function of new molecules involved in sensory axon guidance; and 3) to characterize and clone the mutated gene from a mutant that has defective sensory axon pathways. Overall, our studies are designed to understand the processes involved in promoting and inhibiting axon growth, and patterning the complex arborization patterns of the nervous system. Knowledge of these mechanisms is important for understanding diseases of neural development and the conditions under which axon regeneration after injury can occur. Project Narrative: An understanding of the complex processes involved in promoting and inhibiting neuronal axon growth, and the functions of molecules that guide axons to their correct targets will be crucial for understanding diseases of neural development. Moreover, knowledge of these mechanisms will help to understand the conditions under which axon regeneration after injury can occur.