Structural Polarity Influences Terminal Placement and Competition in Formation of the Calyx of Held

结构极性影响花萼形成中的末端位置和竞争

• 批准号: 8930448
• 负责人: Paul Steven Holcomb
• 金额: $ 3.27万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2016-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930448
• 关键词: Address; Affinity; Age; Animals; Area; Attention; Auditory; Auditory system; Autistic Disorder; Axon; Biological Assay; Biological Models; Brain; Brain Stem; Cell Nucleus; Cell physiology; Cell surface; Cells; Cellular Structures; Cochlea; Comorbidity; Complex; Confocal Microscopy; Cytoplasm; Cytoskeleton; Data; Defect; Dendrites; Development; Diagnosis; Disease; Exhibits; Face; Functional disorder; Growth; Hair Cells; Health; Hour; Human body; Injection of therapeutic agent; Light; Link; Location; Medial; Mediating; Microtubules; Mitosis; Modeling; Movement; Mutation; Nerve Tissue; Nervous system structure; Neuraxis; Neurons; Nuclear; Nuclear Envelope; Organelles; Outcome; Phase; Phosphotransferases; Play; Positioning Attribute; Presbycusis; Proteins; Publishing; Research; Resolution; Retina; Retinal; Retinal Degeneration; Role; Scanning Electron Microscopy; Schizophrenia; Structure; Surface; System; Testing; Three-dimensional analysis; Tissues; Transgenic Mice; Transgenic Organisms; Virus; Work; age related; autism spectrum disorder; cell motility; clinically relevant; deafness; disorder prevention; expectation; nerve supply; nervous system development; neural circuit; neuronal cell body; new technology; novel; planar cell polarity; polarized cell; postnatal; ranpirnase; recombinase; reconstruction; relating to nervous system; selective expression; skills training; synaptogenesis; three dimensional structure; trapezoid body

DESCRIPTION (provided by applicant): Polarity, both in arrangement of cellular processes and intracellular proteins and organelles, is essential to the proper functioning of a wide array o tissues in the human body. This is particularly true in the central nervous system, where polarity dictates cell fate during division, controls cell migration and nuclear movement, and determines the location of axons and dendrites. However, the role of polarity in competition between developing inputs on a single neuron has yet to be examined. Defining the polarity mechanisms that may dictate competition is of significant clinical relevance, as disorders such as autism and schizophrenia are believed to arise from under- or over-pruning of terminals during this phase of development. Additionally, defects in polarity have been shown to be associated with deafness and may potentially play a role in age-related decline in retinal function. Recently, the calyx of Held (CoH) connection to the medial nucleus of the trapezoid body (MNTB) has emerged as a model system for competition; it possesses easily identifiable inputs throughout development, a well-defined single terminal as an endpoint for competition, and a rapid and early developmental timeframe of 48-72 hours from P3 to P6. My preliminary data demonstrates that MNTB cells also exhibit intrasomatic polarity, with an eccentrically located nucleus, extensive nuclear foldin where it faces the cytoplasm, and competing terminals that grow preferentially over the cell surface away from the eccentric nucleus. These qualities make the MNTB:CoH connection ideal for studying the role of polarity in competition. I hypothesize that MNTB neurons express intrasomatic polarity transiently during CoH competition and that intrasomatic polarity extends to the somatic surface to determine the positioning of competing inputs and selection of a single, winning input. To show this, I will utilize the novel technologies of serial block-face scanning electron microscopy (SBEM), automated segmentation of neuronal structures, and three-dimensional reconstruction of neurons and their internal structures. A conditional transgenic mouse line will be used to selectively disrupt nuclear eccentricity within MNTB neurons for comparison with normally developed animals. By combining these approaches, this research will establish the contribution of intrasomatic polarity to terminal placement and competition, which may be applicable to many areas of the developing nervous system. Additionally, these findings may also reveal new avenues of research for diagnosis, treatment and prevention of disorders such as autism and schizophrenia.

描述（由申请人提供）：细胞过程以及细胞内蛋白质和细胞器排列的极性对于人体内多种组织的正常功能至关重要。这在中枢神经系统中尤其如此，在中枢神经系统中，极性在分裂期间决定细胞命运，控制细胞迁移和核运动，并确定轴突和树突的位置。然而，极性在单个神经元上发育输入之间的竞争中的作用还有待研究。定义可能决定竞争的极性机制具有重要的临床意义，因为自闭症和精神分裂症等疾病被认为是在发育的这一阶段中由于末端修剪不足或过度而引起的。此外，极性缺陷已被证明与耳聋有关，并可能在与年龄相关的视网膜功能下降中发挥作用。最近，Held的萼（CoH）连接的内侧核的斜方体（MNTB）已成为一个模型系统的竞争;它拥有容易识别的输入整个发展，一个明确的单一终端作为终点的竞争，和一个快速和早期的发展时间表48-72小时，从P3到P6。我的初步数据表明，MNTB细胞也表现出胞体内极性，偏心定位的细胞核，广泛的核foldin在那里它面临的细胞质，和竞争终端，生长优先超过细胞表面远离偏心核。这些特性使得MNTB：CoH连接成为研究极性在竞争中的作用的理想选择。我假设，MNTB神经元表达胞内极性短暂CoH竞争过程中，胞内极性延伸到躯体表面，以确定竞争的输入和选择一个单一的，获胜的输入的定位。为了证明这一点，我将利用连续块面扫描电子显微镜（SBEM），神经元结构的自动分割，神经元及其内部结构的三维重建的新技术。条件转基因小鼠系将用于选择性破坏MNTB神经元内的核偏心率，以与正常发育的动物进行比较。通过结合这些方法，本研究将建立内的极性终端的位置和竞争，这可能适用于许多领域的发展神经系统的贡献。此外，这些发现还可能揭示诊断，治疗和预防自闭症和精神分裂症等疾病的新研究途径。