Mechanisms of axon guidance during development

发育过程中轴突引导的机制

• 批准号: 7969617
• 负责人: edward giniger
• 金额: $ 127.13万
• 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/7969617
• 关键词: Actins; Adult; Animals; Axon; Biochemical; Biology; Brain; Cancer Etiology; Cell Adhesion; Cell Nucleus; Cell Shape; Cell Surface Receptors; Cell membrane; Cells; Complex; Coupling; Cytoskeleton; Dendrites; Development; Disabled Persons; Disease; Drosophila notch protein; Elements; Embryo; Event; Genetic; Growth; Growth Cones; Health; Image; Learning; Life; Ligands; Link; Malignant Neoplasms; Modification; Molecular; National Institute of Neurological Disorders and Stroke; Nerve; Nervous system structure; Neurons; Notch Signaling Pathway; Pathway interactions; Pattern; Peptide Hydrolases; Population; Process; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Regulation; Rhabdomyosarcoma; Role; Signal Pathway; Signal Transduction; Stroke; Structure; Synapses; Tyrosine; Tyrosine Phosphorylation; abl Oncogene; axon guidance; cell motility; cell type; computerized data processing; embryonic stem cell; genetic manipulation; human disease; interest; leukemia; malignant breast neoplasm; medulloblastoma; neural patterning; notch protein; receptor; relating to nervous system; research study; tissue fixing; trafficking

How is the proper pattern of neural connections established during development? And how is that pattern maintained in the adult nervous system? These are the questions that the Axon Guidance and Neural Connectivity Unit seeks to answer. To understand the mechanisms underlying the establishment of neural connections, we focus on what might be termed the "elementary event" in the process of neural wiring, the mechanism by which a single cell-surface receptor tells a developing neuron where to grow in order to find its synaptic partners. We study a particular cell surface receptor called Notch. Notch is notable because, in addition to directing nerve growth, it also controls the branching of dendrites, the identities of neurons (and many other types of cells), how many neurons are born and whether cells live or die. As such, it controls many aspects of animal development and is responsible for a wide array of human diseases, including some kinds of cancer and stroke. What we learn about Notch in axons, therefore, has implications for biology and health far beyond the particular process we are examining. Previous studies of Notch have focused on a single signaling mechanism for this ubiquitous receptor. We have found, however, that this is only half of the story. About 5% of the Notch protein in the embryo is tyrosine phosphorylated, and this population of molecules associates specifically with an alternate group of downstream effectors, the Abl oncogene and its associated accessory factors, to directly control cell-cell contacts, cell shape and cell migration. We have shown, moreover, that this alternate Notch signaling pathway acts at the plasma membrane (as opposed to the standard signaling pathway, which targets events in the cell nucleus), and that it acts via a protein called Rac that is a direct regulator of the actin cytoskeleton and of cell-adhesion complexes. In growing nerves, the activity of the Notch/Abl/Rac machinery is revealed as regulation of the direction and extent of nerve growth. Current experiments are directed at continuing to elucidate the molecular mechanism of this alternate signaling pathway, and to determine where besides growing axons it may act in biology and disease. We are particularly interested by evidence that the alternate Notch signaling pathway we have discovered may be central to controlling the survival of neural and embryonic stem cells, and that it is key to the mechanism by which activation of Notch can cause cancers, including medulloblastoma, leukemia, rhabdomyosarcoma and breast cancer.

开发过程中如何建立神经联系的正确模式？在成人神经系统中如何保持这种模式？这些是Axon指导和神经连接部门寻求回答的问题。 为了了解建立神经联系的机制，我们将重点放在神经接线过程中可能称为“基本事件”的机制，该机制是单个细胞表面受体告诉开发的神经元的机制，以便在哪里生长以找到其突触伴侣。我们研究了一种称为Notch的特定细胞表面受体。 Notch之所以值得注意，是因为除了指导神经生长外，它还控制着树突的分支，神经元（以及许多其他类型的细胞）的身份，有多少神经元出生以及细胞是否生命或死亡。因此，它控制着动物发育的许多方面，并负责各种人类疾病，包括某些癌症和中风。因此，我们在轴突中了解到的缺口对生物学和健康的影响远远超出了我们正在研究的特定过程。先前对Notch的研究集中在该无处不在的受体的单个信号传导机制上。但是，我们发现这只是故事的一半。胚胎中约有5％的缺口蛋白是酪氨酸磷酸化的，并且该分子群专门与替代下游效应子，ABL OtoCerene及其相关的辅助因子专门与直接控制细胞细胞接触，细胞形状和细胞迁移直接控制。此外，我们已经表明，该替代的凹口信号通路起作用在质膜上（与标准信号通路相反，该途径靶向细胞核中的事件），并且它通过称为RAC的蛋白质作用，该蛋白质是肌动蛋白细胞骨架的直接调节剂和细胞粘附复合物的直接调节剂。在日益增长的神经中，凹口/ABL/RAC机械的活性被揭示为对神经生长的方向和程度的调节。当前的实验旨在继续阐明该替代信号通路的分子机制，并确定除了生长轴突外，它还可以在生物学和疾病中起作用。我们特别感兴趣的是，我们发现的备用凹槽信号传导途径可能是控制神经和胚胎干细胞存活的至关重要的，并且这对于置于癌症的激活可能引起癌症，包括髓母细胞瘤，白血病，rhabdomyosarcoma和乳腺癌的机制是关键。