Proto-oncogenes in Axon Guidance

描述(申请人提供)：这项资助建议研究胚胎运动神经元轴突是如何被引导到它们适当的肌肉目标的。这些细胞直接调节神经系统对呼吸和运动的控制。因此，ALS和SMA等运动神经元疾病对人类的健康和护理具有毁灭性的后果。我们的研究应该为这些细胞是如何发育的提供洞察力，并从长远来看，有助于我们对控制大脑中神经元连接和电路形成的机制的总体理解。在发育过程中，产生的运动神经元亚型表现出不同的细胞迁移模式和对轴突路径的特定偏好。虽然已经在运动神经元亚型中发现了转录因子家族，但对哺乳动物中控制单个运动神经元亚型连通性的分子信号知之甚少。我们的初步研究表明，一系列受体酪氨酸激酶参与轴突导航，其他人已经发现，它们是非神经性组织中的原癌基因。在目标1中，我们将描述EphA和ePhin-A信号如何被用来引导MMCM和LMCI细胞。这些研究将有助于理解轴突引导分子是如何扩展其功能的。在目标2中，我们将研究运动神经元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是如何发展的，重点是EphAs和ePhin的作用--就像存在于运动神经元和感觉神经元轴突上的那样。在目标3中，我们将描述FGFR1在MMCM运动神经元轴突引导中的作用，并研究FGFR1-EphA4受体的“串扰”。这将有助于理解MMCM生长锥体如何整合具有吸引力和排斥性的指导线索。在目标4中，我们将确定ePhin-A GPI锚定蛋白反向信号传递所需的辅助受体，并确定其他GPI锚定蛋白是否作为运动轴突导引分子发挥功能。

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.