Proto-oncogenes in Axon Guidance

描述（由申请人提供）：该基金拟研究胚胎运动神经元轴突如何被引导到其适当的肌肉靶点。这些细胞直接调节神经系统对呼吸和运动的控制。因此，运动神经元疾病如ALS和SMA对人类健康和护理具有破坏性后果。我们的研究应该深入了解这些细胞是如何发育的，并从长远来看有助于我们对控制大脑中神经元连接和回路形成的机制的一般理解。在发育过程中，产生运动神经元亚型，其表现出不同的细胞迁移模式和对轴突通路的特定偏好。虽然运动神经元亚型中的转录因子家族已被确定，但对控制哺乳动物个体运动神经元亚型连接的分子信号知之甚少。我们的初步研究表明，轴突导航中有一个受体酪氨酸激酶家族，其他人发现它是非神经元组织中的原癌基因。在目标1中，我们将表征EphA和肝配蛋白-A信号传导如何用于引导MMCm和LMCI细胞。这些研究将有助于理解轴突导向分子如何扩展其功能库。在目标2中，我们将研究运动和感觉神经元之间的轴突间相互作用，以了解正确的传入和传出通路如何发展，重点是运动和感觉神经元轴突上存在的EphAs和ephrin-As的作用。在目的3中，我们将描述FgfR 1在MMCm运动神经元轴突导向中的作用，并研究FgfR 1-EphA 4受体“串扰”。这将有助于了解如何吸引和排斥的指导线索是由MMCm生长锥集成。在目标4中，我们将确定所需的辅受体的肝配蛋白-A GPI锚定蛋白的反向信号，并确定是否其他GPI锚定蛋白作为运动轴突的指导分子的功能。

DESCRIPTION (provided by applicant): This grant proposes to study how embryonic motor neuron axons are guided to their appropriate muscle targets. These cells directly mediate the nervous system's control of respiration and movement. Thus, diseases of motor neurons such as ALS and SMA have devastating consequences for human health and care. Our studies should provide insight into how these cells develop and over the long term contribute to our general understanding of the mechanisms that control neuronal connectivity and circuit formation in the brain. During development, motor neuron subtypes are generated that exhibit distinct cell migration patterns and specific preferences for axon pathways. Although families of transcription factors have been identified in motor neuron subtypes, less is known about the molecular signals that control the connectivity of individual motor neuron subtypes in mammals. Our preliminary studies have implicated a family of receptor tyrosine kinases in axonal navigation, which others have found are proto-oncogenes in non-neuronal tissues. In aim 1 we will characterize how EphA and ephrin-A signaling is used to guide both MMCm and LMCI cells. These studies will help to understand how axon guidance molecules expand their repertoire of functions. In aim 2 we will examine inter-axonal interactions between motor and sensory neurons to understand how proper afferent and efferent pathways develop, focusing on the role of EphAs and ephrin-As present on motor and sensory neuron axons. In aim 3 we will characterize the role of FgfR1 in MMCm motor neuron axon guidance and study FgfR1-EphA4 receptor "cross-talk". This will help to understand how attractive and repulsive guidance cues are integrated by MMCm growth cones. In aim 4 we will identify coreceptors needed for reverse signaling by the ephrin-A GPI-anchored proteins and determine whether other GPI-anchored proteins function as motor axon guidance molecules.