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方面取得了两项重大的智力进展。该项目的核心工作是了解神经如何生长，以及为什么它们可能无法生长。该实验室之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，以促进动物发育过程中神经的正常生长。问题在于神经生长的详细机制涉及超出任何显微镜分辨率的过程。因此，在过去的一年里，我们转向对生长神经的运动机制（肌动球蛋白细胞骨架）进行计算模拟，试图通过对神经的生化机制如何产生使神经生长的力进行可测试的预测，并处理告诉神经在哪里生长的信息，将我们的成像与遗传学和生物化学联系起来。这取得了惊人的成功；我们根据生物物理学第一原理计算生成的图片看起来与我们在显微镜下看到的蛋白质分布极其相似，并且这种相似性已通过严格的定量分析得到验证。因此，我们可以非常有信心地说，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捕捉到了真实神经在发育中的动物中发现路径时所发生的本质。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为什么神经在疾病中无法生长或维持的问题。在这里，我们发现亨廷顿病中突变的基因 HTT 与我们在早期发育中研究的神经生长机制相同。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 突变体中出现的缺陷是由于 Abl 的过度活性。因此，我们对发育早期初始神经生长所做的分析结果解释了导致晚年神经退行性变的基因突变的后果。