Extrinsic signals required for maintenance of dendrite coverage

维持树突覆盖所需的外在信号

• 批准号: 8535230
• 负责人: JAY Z PARRISH
• 金额: $ 32.61万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535230
• 关键词: Adhesives; Adult; Affect; Afferent Neurons; 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 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

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（由申请人提供）：树突分枝模式是神经元类型的标志，也是神经元功能的关键决定因素，影响神经元可以接收的输入的类型和数量以及神经元处理多个输入的能力。随着动物的生长，许多神经元的树突乔木必须按比例扩张，以维持适当的连接并维持其感受野的覆盖范围。同样，成年神经元中的大部分树突乔木在较长时间内保持稳定，以维持感受野覆盖和连接模式。然而，人们对如何主动维护树突乔木知之甚少。通过遗传筛选，我们发现了突变体，它们在表型上定义了果蝇感觉神经元树突维持的不同外在调节模式。通过这个提议，我们的目标是测试以下假设：（1）局部粘合接触确保树突及其感受野在生长过程中协调扩张，（2）基底衍生信号限制树突结构可塑性，防止树突生长超出正常感受野边界，（3）持续需要基质衍生的营养信号来支持树突的维持。在目标 1 中，我们将定义树突-上皮接触在协调树突乔木和感受野扩展中的作用，并确定调节这些接触的因素。我们将使用基于基因编码的荧光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接触，通过修改上皮中接触位点的分布来测试接触的功能相关性，并分析遗传可能破坏这些接触的突变体。在目标 2 中，我们将定义基质细胞外基质 (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。我们将使用基因编码标记和电子显微镜来描绘正常发育期间和维持缺陷突变体中 ECM 组织和分布的变化。此外，我们将确定 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通路，调节树突维持的营养信号传导。总而言之，这些研究将阐明树突及其基质在生长过程中协调生长的机制，确保维持树突覆盖。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病，但人们对树突乔木如何维持知之甚少。从这项工作中获得的基本见解预计对于理解不同类型的外在信号在树突维持中的正常发育作用以及扰乱这些外在信号的后果具有重要意义。