Delta-Notch Signaling by Intermediate Neuronal Progenitors: Live Imaging

中间神经元祖细胞的 Delta-Notch 信号传导：实时成像

• 批准号: 7904850
• 负责人: Robert F Hevner
• 金额: $ 24.38万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904850
• 关键词: Adaptive Behaviors; Adolescent; Apical; Area; Autistic Disorder; Behavioral; Binding; Brain; Cell Communication; Cell physiology; Cells; Cerebral cortex; Cerebrum; Characteristics; Color; Communication; Complex; Development; Disease; Dominant-Negative Mutation; Drug abuse; Embryo; Emotional; Epilepsy; Equilibrium; Foundations; Future; Gene Family; Generations; Goals; Grant; Image; Imaging Techniques; Immunofluorescence Immunologic; Immunolabeling Technics; In Situ Hybridization; Life; Light; Limbic System; Link; Location; Maintenance; Mediating; Mental Depression; Mental Retardation; Microscopy; Modeling; Molecular; Molecular Profiling; Monitor; Motor; Neocortex; Neurologic; Neurons; Pathway interactions; Photons; Population Heterogeneity; Predisposition; Process; Production; Radial; Reporter Genes; Role; Schizophrenia; Sensory; Signal Transduction; Signaling Molecule; Site; Slice; Social Interaction; Source; Stem cells; Testing; Time; Tissues; Transgenic Organisms; Update; Ventricular; adult neurogenesis; base; cell type; cellular imaging; cognitive function; daughter cell; hippocampal pyramidal neuron; in vivo; inhibitor/antagonist; innovation; motivated behavior; nerve stem cell; neural circuit; neurogenesis; neuronal cell body; neuropsychiatry; notch protein; novel; overexpression; progenitor; public health relevance; repaired; research study; secretase; stem; subventricular zone; transcription factor

DESCRIPTION (provided by applicant): The cerebral cortex is critically important for higher motor, sensory, and cognitive functions of the brain, such as social interactions and communication, and together with subcortical areas of the limbic system, regulate complex emotional and motivated behaviors. Disorders of cortical development underlie neuropsychiatric illnesses such as autism, schizophrenia, and depression, and the abnormal developmental trajectories of cortical and limbic circuits may impact adaptive behaviors such as drug abuse. The objective of this proposal is to investigate the molecular and cellular mechanisms regulating the normal production of neurons in the cerebral cortex, which arise from a heterogeneous population of stem/progenitor cells located in the ventricular zone of the neocortex and essential for correct neural circuit trajectories. Cell-cell interactions mediated by Delta-Notch signaling are required for both producing the correct number of neurons and maintaining the progenitor pool during corticogenesis, although essential details remain unknown. Importantly, the specific cellular and molecular interactions between different cell types have not been delineated. We hypothesize that different cell types signal to each other through evolutionary diversified components of Delta-Notch gene families, and that a novel Delta-mediated interaction between a subset of progenitors controls the balance between neuron production and progenitor maintenance. We will first determine the cortical cell types that express different Delta-Notch signaling components using combined in situ hybridization/immunolabeling techniques in conjunction with transgenic markers of defined cell types. We have developed a novel 2-color 2-photon live-cell imaging technique that serves as major innovation, allowing us to determine the cellular basis of Delta-Notch signal transduction in dynamically behaving cells that will be tested in functional experiments. The results of this exploratory R21 grant will provide the foundation of a sophisticated new model we propose that encompasses multiple sources of cell-cell interactions regulated by diverse Delta-Notch signaling in the developing cortex. Future studies will examine this mechanism in developing subcortical regions, and in adolescent and adult neurogenesis. PUBLIC HEALTH RELEVANCE: Neurological and behavioral diseases and disorders, such as autism, schizophrenia and susceptibility to drug abuse are thought to arise from developmental deficits in the generation/trajectory/connectivity of neurons in the brain. If we know how these neurons normally develop, then we will be better able to develop strategies aimed at repairing or replacing them when their normal development goes awry.

描述（由申请人提供）：大脑皮层对于大脑的更高运动，感觉和认知功能至关重要，例如社交互动和交流，以及边缘系统的下皮层区域，调节复杂的情感和动机行为。皮质发育的疾病是神经精神疾病的基础，例如自闭症，精神分裂症和抑郁症，以及皮质和边缘回路的异常发育轨迹可能会影响适应性行为，例如药物滥用。该提案的目的是研究调节大脑皮质中神经元正常产生的分子和细胞机制，这些机制是由位于新皮层心室中心区域的异质群/祖细胞的异质群引起的，对于正确的神经回路轨迹必不可少。通过未知的细节尚不清楚，通过产生正确数量的神经元和维持祖细胞池的介导的细胞 - 细胞相互作用是产生正确数量的神经元和维持祖细胞池的细胞相互作用。重要的是，尚未描绘出不同细胞类型之间的特定细胞和分子相互作用。我们假设不同的细胞类型通过Delta-Notch基因家族的进化多样化成分相互信号，并且新型的Delta介导的祖细胞组之间的相互作用控制着神经元产生与祖细胞维持之间的平衡。我们将首先确定使用原位杂交/免疫标记技术与定义细胞类型的转基因标记结合使用的原位杂交/免疫标记技术来表达不同的Delta-Notch信号传导组件。我们已经开发了一种新型的2色2-Photon活性成像技术，该技术是主要的创新，使我们能够确定在功能实验中将测试的动态行为细胞中delta-notch信号转导的细胞基础。该探索性R21赠款的结果将为我们提出的复杂新模型的基础提供基础，该模型涵盖了开发皮层中由不同的Delta-notch信号传导调节的细胞 - 细胞相互作用的多种来源。未来的研究将研究这种机制，以发展皮层下区域以及青少年和成人神经发生。公共卫生相关性：神经和行为疾病和疾病，例如自闭症，精神分裂症和对药物滥用的易感性，是由大脑中神经元的产生/轨迹/连通性的发育缺陷引起的。如果我们知道这些神经元通常是如何发展的，那么我们将更好地制定旨在在正常发展出现时修复或替换它们的策略。