Extrinsic signals required for maintenance of dendrite coverage

维持树突覆盖所需的外在信号

基本信息

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
项目类别：
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&apos 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

项目摘要

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.