Mechanisms of axon guidance during development

发育过程中轴突引导的机制

• 批准号: 10460392
• 负责人: edward giniger
• 金额: $ 77.66万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460392
• 关键词: Actomyosin; Animals; Attention; Axon; Biochemical; Biochemistry; Biological Assay; Biophysics; Cell physiology; Computer Simulation; Cytoskeleton; Defect; Development; Disease; Drosophila genus; Epithelial; Gene Proteins; Genes; Genetic; Growth; Growth Cones; Huntington Disease; Image; Individual; Life; Microscope; Modeling; Molecular; Morphogenesis; Morphology; Motor; Mutate; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Output; Paper; Pathway interactions; Pattern; Phosphotransferases; Preparation; Process; Proteins; Proto-Oncogene Proteins c-abl; Publications; Signal Pathway; Signal Transduction; Structure; Surface; Vertebrates; Work; axon growth; axon guidance; cell motility; molecular modeling; mutant; notch protein; protein distribution; receptor

In the past year, we have made two significant intellectual advances in our analysis of axon growth and guidance. The central effort in this project is to understand how nerves grow, and why they may fail to grow. Previous work from the lab combined live imaging of single growing axons with genetic and biochemical analysis of genes and proteins that promote proper nerve growth during the development of the animal. The problem has been that the detailed mechanism of nerve growth involves processes that lie beyond the resolving power of any microscope. In the past year, therefore, we have turned to computational simulations of the motor machinery of the growing nerve, the actomyosin cytoskeleton, to try to connect our imaging with our genetics and biochemistry by generating testable predictions for how the biochemical machinery of the nerve generates the force to make the nerve grow, and processes the information that tells the nerve where to grow. This has been astonishingly successful; the pictures we generate computationally from biophysical first principles look extremely similar to the protein distributions we see in the microscope, and that similarity has been validated by rigorous quantitative analysis. 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. These computational papers are currently in preparation for publication. In parallel, we also turned our attention to the problem of why nerves fail to grow, or to be maintained, in disease. Here we found that the gene that is mutated in Huntingtons Disease, HTT, is a piece of the same nerve growth machinery we have been studying in early development. Indeed, HTT is a repressor of the Abl kinase that is the key regulator of actomyosin during nerve growth, and the defects that occur in an htt mutant are due to overactivity of Abl. Thus, the analysis we have done of initial nerve growth early in development turns out to explain the consequences of mutating a gene that causes neurodegeneration late in life.

在过去的一年里，我们在轴突生长和引导的分析中取得了两个重大的智力进步。这个项目的核心工作是了解神经是如何生长的，以及为什么它们可能无法生长。该实验室以前的工作将单个生长轴突的实时成像与基因和蛋白质的遗传和生化分析相结合，这些基因和蛋白质在动物发育过程中促进神经正常生长。问题是，神经生长的详细机制涉及的过程超出了任何显微镜的分辨率。因此，在过去的一年里，我们转向了对生长神经的运动机制（肌动球蛋白细胞骨架）的计算机模拟，试图通过生成可测试的预测来将我们的成像与我们的遗传学和生物化学联系起来，预测神经的生物化学机制如何产生使神经生长的力量，并处理告诉神经生长位置的信息。这已经取得了巨大的成功;我们从生物物理学第一原理计算生成的图像看起来与我们在显微镜下看到的蛋白质分布非常相似，并且这种相似性已经通过严格的定量分析得到了验证。因此，我们可以很有信心地说，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，确实抓住了真实的神经在发育中的本质。这些计算论文目前正在准备出版。与此同时，我们也将注意力转向了为什么神经在疾病中不能生长或维持的问题。在这里，我们发现亨廷顿病中突变的基因HTT是我们在早期发育中研究的相同神经生长机制的一部分。事实上，HTT是Abl激酶的阻遏物，Abl激酶是神经生长过程中肌动球蛋白的关键调节因子，而HTT突变体中发生的缺陷是由于HTT的过度活性。因此，我们对发育早期的初始神经生长所做的分析结果解释了导致生命后期神经退行性变的基因突变的后果。