Neuronal Transdifferention in vivo: Mechanism and Potential

体内神经元转分化：机制和潜力

基本信息

批准号：
8670308
负责人：
Angeles Badell Ribera
金额：
$ 33.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8670308
关键词：
Adopted Adoption Afferent Neurons Affinity Behavior Brain-Derived Neurotrophic Factor Cell Culture Techniques Cell Line Cell Transplantation Cells Characteristics Data Embryo Environment Ganglia Gene Expression Genes Genetic Transcription Hour Human Image Immigration In Situ Incidence Knock-out Larva Lead Life Location Longevity Maintenance Mediating Methods Mitotic Modeling Molecular Molecular Profiling Morphology NGFR Protein Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Peripheral Nervous System Phenotype Plastics Positioning Attribute Post-Translational Protein Processing Property Proteins Regulation Reporter Sensory Deprivation Signal Transduction Sodium Channel Source Spinal Ganglia Stem cells Sympathetic Ganglia Testing Work Zebrafish adult neurogenesis base cell type ganglion cell in vivo knock-down mRNA Expression migration nervous system disorder neurogenesis neuronal cell body neurotrophic factor novel public health relevance receptor research study time use transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Although adult neurogenesis provides new neurons to some regions of the central nervous system, whether this also occurs in the peripheral nervous system is not known. Our recent in vivo studies in zebrafish larvae suggest that another mechanism might serve as a source of new neurons for the peripheral nervous system. We have found that a subset of differentiated dorsal root ganglion neurons to migrate new ventral locations and acquire new morphologies and molecular properties. The novel characteristics are all indicative of adoption of a new identity as a sympathetic ganglion neuron. Importantly, dorsal root ganglion neurons can acquire sympathetic ganglion neuron-like properties in wild type larvae under control conditions. However, sensory deprivation and blockade of a specific sodium channel, Nav1.6a, increases the number of dorsal root ganglion neurons that acquire a new identity, i.e., transdifferentiate. Even though Nav1.6a is normally expressed in several neurons, the channel's activity is required in only one cell type for maintenance of dorsal root ganglion identity. Interestingly, that cell type is not the dorsal root ganglion neuron but rather n earlier appearing sensory neuron, known as the Rohon-Beard cell. Our previous work has also shown that the neurotrophin BDNF mediates that Nav1.6a-activity-dependent signal. Recently, we have found that differentiated dorsal root ganglion neurons migrate to yet other locations besides the sympathetic ganglion, raising the possibility that migratory dorsal root ganglion neurons might assume other fates than that of the sympathetic ganglion neuron. Here we propose three Specific Aims that will provide important information about the underlying mechanisms involved in the relevant BDNF- dependent signaling. In Aim 1, we identify the cell types that secrete and respond to the relevant BDNF. In Aim 2, we determine the full range of cellular identities that migratory dorsal root ganglion neurons may adopt. Aim 3 experiments identify gene expression changes that underlie BDNF's regulation of the migratory phenotype of differentiated DRG neurons. The results will provide information that could lead to alternative strategies for treatment of neurodegenerative conditions.

描述（由申请人提供）：虽然成体神经发生为中枢神经系统的某些区域提供了新的神经元，但尚不清楚这是否也发生在周围神经系统中。我们最近对斑马鱼幼虫的体内研究表明，另一种机制可能作为周围神经系统新神经元的来源。我们发现分化的背根神经节神经元的一个子集可以迁移新的腹侧位置并获得新的形态和分子特性。这些新特征都表明采用了交感神经节神经元的新身份。重要的是，在对照条件下，野生型幼虫的背根神经节神经元可以获得类似交感神经节神经元的特性。然而，感觉剥夺和特定钠通道 Nav1.6a 的阻断会增加获得新身份（即转分化）的背根神经节神经元的数量。尽管 Nav1.6a 通常在多个神经元中表达，但只有一种细胞类型需要该通道的活性来维持背根神经节的身份。有趣的是，这种细胞类型不是背根神经节神经元，而是早期出现的感觉神经元，称为罗洪-比尔德细胞。我们之前的工作还表明，神经营养蛋白 BDNF 介导 Nav1.6a 活性依赖性信号。最近，我们发现分化的背根神经节神经元迁移到交感神经节以外的其他位置，这增加了迁移的背根神经节神经元可能承担与交感神经节神经元不同的命运的可能性。在这里，我们提出了三个具体目标，这些目标将提供有关相关 BDNF 依赖性信号传导所涉及的底层机制的重要信息。在目标 1 中，我们确定了分泌并响应相关 BDNF 的细胞类型。在目标 2 中，我们确定了迁移性背根神经节神经元可能采用的全部细胞特性。目标 3 实验确定了 BDNF 调节分化 DRG 神经元迁移表型的基因表达变化。研究结果将提供可能导致神经退行性疾病治疗替代策略的信息。