Signaling Pathways That Differentiate Dendrite and Axon Development

描述(申请人提供)：神经系统中的信息处理依赖于树突和轴突的分离。然而，关于树突和轴突如何发育成不同的隔室，人们知之甚少。这项应用的长期目标是确定在神经回路的发展过程中神经元分区是如何实现的，以及该过程中的缺陷如何导致神经和精神疾病。这项应用的目的是描绘分离树突和轴突发育的信号通路。最近对果蝇的遗传学研究表明，成纤维细胞生长因子受体不同地控制树突和轴突的发育。这一应用的中心假设是，成纤维细胞生长因子受体激活不同的信号通路，以不同的方式控制树突和轴突的发育。我们将通过三个特定的目标来验证这一假说：1)确定成纤维细胞生长因子受体控制树突特异性发育的信号通路；2)确定成纤维细胞生长因子受体是否通过与树突发育不同的途径调节轴突发育；3)确定成纤维细胞生长因子受体在树突和轴突分化发育中的作用在哺乳动物神经元中是否保守。该方法具有创新性，因为它利用遗传分析来研究体内树突和轴突之间的发育差异，并结合果蝇和哺乳动物系统来研究进化保守的机制。这项拟议的研究具有重要意义，因为它有望促进对树突和轴突差异发育背后的信号机制的了解。需要这些知识来制定策略，允许在疾病条件下或在动物模型中优先或特定地处理树突或轴突的发育，以询问神经系统的功能。 与公共健康相关：神经元的信息接收(树突)和发送(轴突)部分是如何形成的，人们知之甚少。这一知识很重要，因为许多神经和精神疾病涉及这两个神经元部分的缺陷。这项拟议的研究将提供必要的知识，以开发具有亚细胞精度的治疗策略，以纠正人类疾病中有缺陷的树突和轴突。

DESCRIPTION (provided by applicant): Information processing in the nervous system relies on the separation of dendrites and axons. However, little is known about how dendrites and axons develop into distinct compartments. The long-term goal of this application is to define how neuronal compartmentalization is achieved during the development of neural circuits and how defects in that process lead to neurological and psychiatric diseases. The objective of this application is to delineate the signaling pathways that separate dendrite and axon development. Recent genetic studies on Drosophila have demonstrated that the fibroblast growth factor (FGF) receptors differentially control dendrite and axon development. The central hypothesis of this application is that the FGF receptors activate distinct signaling pathways to differentially control dendrite and axon development. We will test this hypothesis by pursuing three specific aims: 1) ) Identify the signaling pathway through which FGF receptors control dendrite-specific development; 2) Determine whether FGF receptors regulate axon development through pathways different from dendrite development; 3) Determine whether the roles of FGF receptors in the differential development of dendrites and axons are conserved in mammalian neurons. The approach is innovative because it takes advantage of genetic analysis to investigate the developmental differences between dendrites and axons in vivo and combines both Drosophila and mammalian systems to study evolutionarily conserved mechanisms. The proposed research is significant because it is expected to advance knowledge of the signaling mechanisms underlying the differential development of dendrites and axons. That knowledge is needed to develop strategies that will allow preferential or specific manipulations of dendrite or axon development in disease conditions and in animal models to interrogate the functions of the nervous system. PUBLIC HEALTH RELEVANCE: How the information-receiving (dendrites) and -sending (axons) parts of neurons form is poorly understood. This knowledge is important because many neurological and psychiatric diseases involve defects in these two parts of neurons. The proposed research will provide the knowledge needed to develop therapeutic strategies having subcellular precision to correct defective dendrites and axons in human diseases.