Extracellular Matrix and Axonal Guidance in C. elegans

我们的长期目标是找出迁移轴突如何响应引导线索，并被引导到 他们的目标一个功能正常的神经系统需要神经元的连接， 详细而刻板的模式。这种特异性依赖于神经元对通路的选择， 生长锥我们专注于C中特定轴突的指导。elegans模型系统。如在 包括人类在内的其他生物体，迁移轴突对细胞外 引导线索我们并不十分了解轴突的机制， 向一个引导线索的来源迁移，而其他的迁移。轴突如何改变它们的 对线索的反应，同时经历形态变化，如分支，转向， 突触的形成也没有得到很好的理解。通过基因筛选，我们发现了几种 分子可能调节轴突反应，现在建议研究机制， 它们的作用：（i）我们发现，在响应β-6/netrin和β-1/slit的指导提示时，轴突 导向受体β 1 -40/DCC不对称定位并募集蛋白质如β 1 -10， 可以促进轴突生长(ii)建议将β-6-连接的β-40信号传导到不对称的 受体的定位。我们已经发现了突变的α-6和α-40，可能会改变 连接的α-40构象，我们正在研究这些变化如何改变α-40的定位， 40，并可导致不同方向的生长。(iii)我们发现，α-80可以影响轴突受体， 活性，我们正在探索这种分子是否会影响非对称定位， 与引导线索的来源相关的受体。(iv)我们已经证明了两种分子，CLEC- 38和RPM-1，负性调节β 1 -40和β 1 -5和SAX-3轴突导向受体， 分别这些分子也积极调节突触前发育，表明 这有助于协调这些活动。(v)我们发现证据表明 靶神经元分泌的乙酰胆碱通过控制CLEC-38调节轴突导向受体 RPM-1活性。这种信号传导可以提供一种手段，通过这种手段，靶点可以调节细胞的功能。 接近轴突的发展。我们希望将我们对这些不同分子的研究扩展到 有助于阐明促进特定轴突对引导线索反应的机制，从而获得 更好地理解神经系统功能的神经回路是如何发展的。

Our long-term goal is to find out how migrating axons respond to guidance cues and are guided to their targets. A functional nervous system requires neuronal connections to be made in a highly detailed and stereotypic pattern. This specificity depends on the selection of pathways by neuronal growth cones. We focus on the guidance of specific axons in the C. elegans model system. As in other organisms, including humans, migrating axons have different responses to extracellular guidance cues. We do not have a very good idea of the mechanisms that permit some axon to migrate towards a source of a guidance cue, while other migrate away. How axons change their responsiveness to cues while undergoing morphological changes, such as branching, turning, and synapse formation is also not well understood. Using genetic screens we have identified several molecules likely to regulate axon responses, and now propose to investigate the mechanisms by which they act: (i) We found that in response to UNC-6/netrin and SLT-1/slit guidance cues the axon guidance receptor UNC-40/DCC is asymmetrically localized and recruits proteins such as MIG-10, which can promote axon outgrowth. (ii) UNC-6-ligated UNC-40 is proposed to signal the asymmetric localization of the receptor. We have found mutations in UNC-6 and UNC-40 that may alter the ligated UNC-40 conformation and we are studying how these changes alter the localization of UNC- 40 and can cause outgrowth in different directions. (iii) We found UNC-80 affects axon receptor activity and we are exploring whether this molecules influences the asymmetric localization of receptors relative to the source of the guidance cues. (iv) We have shown that two molecules, CLEC- 38 and RPM-1, negatively regulate the UNC-40 and the UNC-5 and SAX-3 axon guidance receptors, respectively. These molecules also positively regulate presynaptic development, suggesting a link between these processes that could help coordinate their activities. (v) We find evidence that acetylcholine secreted by target neurons regulates axon guidance receptors by controlling CLEC-38 and RPM-1 activity. This signaling could provide a means through which the targets regulate the development of approaching axons. We hope to extend our studies of these different molecules to help elucidate mechanisms that promote specific axon responses to guidance cues, thereby gaining a better understanding of how the neural circuits that underlie nervous system function develop.