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.

在发育过程中，正确的神经连接模式是如何建立的？这种模式是如何在成人神经系统中维持的呢？这些都是轴突引导和神经连接单元试图回答的问题。