Mechanisms of axon guidance during development

在过去的一年里，我们发表了三篇实验论文和一篇综述文章，建立了轴突生长和引导机制的新模型。在过去的几年里，我们使用了肌动蛋白动力学的计算模拟来剖析生长锥肌动蛋白组织的调节，我们之前在体内生长的轴突中进行了实验量化。这些模拟揭示了控制生长轴突中肌动球蛋白细胞骨架分布的意想不到的生物物理机制（去年秋天发表在两篇论文中，并在今年春天发表的一篇综述中进行了总结）。作为对这些假设的检验，我们随后进行了一系列实验，挑战了计算模型的一个意想不到的、也许是反直觉的预测。正如去年春天发表在另一篇论文中的那样，在体内进行的基因操作和成像证实了计算预测，有力地支持了潜在的假设。因此，我们可以满怀信心地说，我们提出的关于神经如何生长以及它们如何知道在哪里生长的详细分子模型，确实抓住了真实神经在动物发育过程中所发生的本质。

In the past year, we have published three experimental papers and a review article that establish a novel model for the mechanism of axon growth and guidance. Over the past several years, we have used computational simulations of actin dynamics to dissect the modulation of growth cone actin organization that we had previously quantified experimentally in a growing axon in vivo. These simulations uncovered unexpected biophysical mechanisms that control the distribution of the actomyosin cytoskeleton in a growing axon (published in two papers last fall, and summarized in a review published this spring). As a test of these hypotheses, we then performed a series of experiments challenging an unexpected and perhaps counter-intuitive prediction of the computational model. As published in an additional paper last spring, genetic manipulations and imaging performed in vivo confirmed the computational predictions, strongly supporting the underlying hypothesis. We can therefore say with great confidence that the detailed molecular model we have proposed for how nerves grow, and how they know where to grow, indeed captures the essence of what goes on in a real nerve as it finds its way through the developing animal. In parallel with this project, we performed two collaborative projects that advance our understanding of how the molecular machinery of cytoskeletal reorganization is regulated by a specific cell surface signaling receptor. We found that the receptor, Notch, controls neuronal morphogenesis by regulating Abl kinase in two different, non-axonal contexts in the fly, rotation of photoreceptor neurons during eye development and regulation of dendritic branching. These observations demonstrate that the morphogenetic interaction of Notch with Abl that we have investigated in axons has more general application in multiple processes of neuronal cell biology.