Extrinsic signals required for maintenance of dendrite coverage

维持树突覆盖所需的外在信号

• 批准号: 8322031
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322031
• 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）：树突树木化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。随着动物的成长，许多神经元的树突arb arbor必须按比例扩展，以维持适当的连通性并维持其接受场的覆盖范围。同样，成年神经元中的大部分树突arbors在长时间内保持稳定，以保持接收场的覆盖范围和连通性模式。但是，对于如何积极维护树突不足，知之甚少。使用遗传筛选，我们已经确定了表型从果蝇感觉神经元中表型定义枝晶维持的外在调节模式的突变体。通过该建议，我们旨在测试（1）局部粘合剂接触的假设确保树突及其在增长时期的接收领域的协调膨胀，（（2）底物衍生的信号限制了树突结构可塑性，防止了树突的增长，从而超出了正常的接收场范围，并且（3）良好的维持良好的滋养性滋养性滋养性。在AIM 1中，我们将定义树突上皮接触在协调树突植物和接受场扩张中的作用，并确定调节这些接触的因素。我们将使用遗传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接触，测试接触位点在上皮细胞中的接触位点的分布，并分析可能破坏这些接触的遗传突变体的功能相关性。在AIM 2中，我们将定义底物细胞外基质（ECM）修饰在限制树突生长并确保维持接受场覆盖范围中的作用。我们将使用遗传编码的标记和电子显微镜来描述正常发育过程中ECM组织和分布的变化，以及维持缺陷的突变体。此外，我们将确定ECM修改所需的基材衍生的因素。在AIM 3中，我们将定义一种神经元非自治途径，该途径调节营养信号以维持树突状态。总的来说，这些研究将阐明树突及其底物在生长过程中协调的机制，从而确保维持树突覆盖范围。尽管树突形态的缺陷与各种发育和退化性疾病有关，包括智力低下，癫痫，精神分裂症和帕金森氏病，但对如何维持树突不足的了解知之甚少。预计从这项工作中获得的基本见解对于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对这些外部信号扰动的后果具有重要意义。