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.

在过去的一年中，我们在分析轴突增长和指导方面取得了两个重大的智力进步。该项目的核心努力是了解神经如何成长，以及为什么它们可能无法成长。实验室的先前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了适当的神经生长。问题是，神经增长的详细机制涉及超出任何显微镜解决力的过程。因此，在过去的一年中，我们转向了对神经不断增长的运动机械的计算模拟，肌动蛋白细胞骨架的运动机制，试图通过为神经的生化机械产生可使神经生长的力量生长的能力如何产生能力而增长的信息，从而将我们的成像与我们的遗传学和生物化学联系起来。这是惊人的成功。我们从生物物理第一原理上生成计算的图片看起来与我们在显微镜中看到的蛋白质分布非常相似，并且通过严格的定量分析来验证相似性。因此，我们可以充满信心地说，我们提出了有关神经如何成长的详细分子模型，以及他们如何知道在哪里生长，确实捕捉了真正神经中发生的事情的本质，因为它通过发育中的动物发现了自己的方式。这些计算论文目前正在准备出版。同时，我们也将注意力转向了为什么神经无法在疾病中生长或维持的问题。在这里，我们发现在Huntingtons病中突变的基因HTT是我们在早期发育方面一直在研究的相同神经生长机制的一部分。实际上，HTT是ABL激酶的阻遏物，它是神经生长过程中肌动蛋白的关键调节剂，HTT突变体中发生的缺陷是由于ABL的过度活动性。因此，我们对发育早期初始神经生长进行的分析证明了突变导致生命后期神经退行性的基因的后果。