Extrinsic signals required for maintenance of dendrite coverage

维持树突覆盖所需的外在信号

• 批准号: 8910794
• 负责人: JAY Z PARRISH
• 金额: $ 33.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910794
• 关键词: Adhesives; Adult; Affect; Afferent Neurons; Alzheimer' s Disease; Animals; Anterior; Astrocytes; Basement membrane; Bipolar Disorder; Body Regions; Collagen Type IV; Complex; Coupling; Defect; Degenerative Disorder; Dendrites; Development; Disease; Drosophila genus; Electron Microscopy; Ensure; Epilepsy; Epithelial; Epithelial Cells; Epithelium; Etiology; Extracellular Matrix; Fluorescence; Genes; Genetic; Genetic Epistasis; Genetic Screening; Growth; Maintenance; Mediating; Mediator of activation protein; Mental Retardation; Modeling; Modification; Molecular; Monitor; Morphogenesis; Morphology; Mutation; Nervous system structure; Neurons; Parkinson Disease; Pathology; Pathway interactions; Pattern; Peripheral; Play; Process; Proteins; Public Health; Regulation; Research; Resolution; Role; Schizophrenia; Signal Pathway; Signal Transduction; Sirolimus; Site; Specialized Epithelial Cell; Substrate Interaction; Synapses; System; Testing; Therapeutic; Time; Work; base; developmental disease; ganglion cell; gene function; genetic analysis; human disease; in vivo; insight; mutant; nervous system disorder; prevent; receptive field; research study; sensor; synaptogenesis; temporal measurement

DESCRIPTION (provided by applicant): Dendrite arborization patterns are a hallmark of neuronal type and a critical determinant of neuronal function, influencing the type and number of inputs that a neuron can receive as well as the ability of a neuron to process multiple inputs. As animals grow, dendrite arbors of many neurons must expand proportionally to sustain proper connectivity and maintain coverage of their receptive field. Likewise, large portions of dendrite arbors in adult neurons are stable over extended periods of time to maintain receptive field coverage and patterns of connectivity. However, little is known about how dendrite arbors are actively maintained. Using genetic screens, we have identified mutants that phenotypically define different modes of extrinsic regulation of dendrite maintenance in Drosophila sensory neurons. With this proposal, we aim to test the hypotheses that (1) localized adhesive contacts ensure coordinated expansion of dendrites and their receptive field during times of growth, (2) substrate-derived signals restrict dendrite structural plasticity, preventing dendrite growth beyond normal receptive field boundaries, and (3) substrate-derived trophic signals are continuously required to support dendrite maintenance. In Aim 1, we will define roles of dendrite-epithelial contacts in coordinating dendrite arbor and receptive field expansion, and identify factors that modulate these contacts. We will monitor these contacts in vivo using a genetically-encoded fluorescence-based proximity sensor, characterize the contacts at high resolution using electron microscopy, test the functional relevance of the contacts by modifying the distribution of the contact sites in the epithelium, and analyze genetic mutants that likely disrupt these contacts. In Aim 2, we will define roles of substrate extracellular matrix (ECM) modification in restricting dendrite growth and ensuring maintenance of receptive field coverage. We will use genetically encoded markers and electron microscopy to delineate changes in ECM organization and distribution during normal development and in maintenance-defective mutants. Additionally, we will identify substrate-derived factors required for ECM modifications. In Aim 3, we will define a neuron non-autonomous pathway that regulates trophic signaling for dendrite maintenance. Altogether, these studies will elucidate mechanisms by which growth of dendrites and their substrate are coordinated during growth, ensuring maintenance of dendrite coverage. Although defects in dendrite morphology are associated with a variety of developmental and degenerative disorders, including mental retardation, epilepsy, schizophrenia, and Parkinson's disease, little is known about how dendrite arbors are maintained. Basic insights gained from this work are expected to be of significance for understanding the normal developmental role of different types of extrinsic signals in dendrite maintenance as well as the consequences of perturbing these extrinsic signals.

描述(申请人提供)：树突分枝模式是神经元类型的标志和神经元功能的关键决定因素，影响神经元可以接受的输入的类型和数量以及神经元处理多个输入的能力。随着动物的成长，许多神经元的树突必须按比例扩张，以维持适当的连通性，并保持其感受野的覆盖。同样，成年神经元中的大部分树突树枝在较长的时间内保持稳定，以保持接受野的覆盖和连接模式。然而，关于树枝乔木是如何被积极维护的，人们知之甚少。利用遗传筛选，我们已经确定了突变体，这些突变体在表型上定义了果蝇感觉神经元树突维持的不同外部调节模式。根据这一建议，我们的目标是检验以下假设：(1)局部粘性接触确保树突及其接受场在生长期间协调扩张，(2)底物衍生信号限制树突结构可塑性，防止树枝生长超过正常接受野边界，以及(3)底物衍生营养信号持续需要支持树突维持。在目标1中，我们将定义树突-上皮接触在协调树突枝和感受野扩展中的作用，并确定调节这些接触的因素。我们将使用基因编码的基于荧光的接近传感器在体内监测这些接触，使用电子显微镜以高分辨率表征这些接触，通过改变接触部位在上皮中的分布来测试接触的功能相关性，并分析可能破坏这些接触的遗传突变。在目标2中，我们将确定底物细胞外基质(ECM)修饰在限制树突生长和确保维持感受野覆盖方面的作用。我们将使用遗传编码标记和电子显微镜来描绘正常发育过程中ECM组织和分布的变化以及维护缺陷突变体的变化。此外，我们还将确定ECM修饰所需的底物衍生因子。在目标3中，我们将定义一条神经元非自主途径，调节树突维持的营养信号。总之，这些研究将阐明树突及其底物在生长过程中协调生长的机制，以确保维持树枝的覆盖率。尽管树突形态缺陷与多种发育和退行性疾病有关，包括智力低下、癫痫、精神分裂症和帕金森氏病，但树突是如何维持的知之甚少。从这项工作中获得的基本见解有望对理解不同类型的外部信号在树突维持中的正常发育作用以及干扰这些外部信号的后果具有重要意义。