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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）：虽然成人神经发生为中枢神经系统的某些区域提供新的神经元，但这是否也发生在外周神经系统中尚不清楚。我们最近在斑马鱼幼体中的体内研究表明，另一种机制可能是外周神经系统新神经元的来源。我们发现一个分化的背根神经节神经元的子集迁移到新的腹侧位置，并获得新的形态和分子特性。这些新的特征都表明采用了作为交感神经节神经元的新身份。重要的是，背根神经节神经元可以获得交感神经节神经元样的属性在野生型幼虫在控制条件下。然而，感觉剥夺和特定钠通道Nav1.6a的阻断增加了获得新身份的背根神经节神经元的数量，即，转分化尽管Nav1.6a通常在几个神经元中表达，但仅在一种细胞类型中需要通道的活性来维持背根神经节的特性。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Rohon-Beard细胞。我们之前的工作也表明，神经营养因子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，提高了迁移背根神经节神经元可能承担比交感神经节神经元的其他命运的可能性。在这里，我们提出了三个具体的目标，将提供重要的信息，涉及相关的BDNF依赖性信号的潜在机制。在目标1中，我们确定了分泌和响应相关BDNF的细胞类型。在目标2中，我们确定了迁移背根神经节神经元可能采用的全部细胞身份。目的：通过3个实验来确定BDNF调节分化的DRG神经元迁移表型的基因表达变化。研究结果将提供信息，可能导致治疗神经退行性疾病的替代策略。