Neuronal Transdifferention in vivo: Mechanism and Potential

描述(申请人提供)：尽管成人神经发生为中枢神经系统的某些区域提供了新的神经元，但这种情况是否也发生在周围神经系统尚不清楚。我们最近对斑马鱼幼虫进行的体内研究表明，另一种机制可能是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，获得新的形态和分子特性。这些新的特征都表明采用了一个新的身份作为交感神经节神经元。重要的是，在对照条件下，背根神经节神经元可以在野生型幼虫中获得交感神经节神经元样属性。然而，感觉剥夺和阻断特定的钠通道Nav1.6a，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，但只有一种细胞类型需要该通道的活动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，而是更早出现的感觉神经元，称为罗洪-比尔德细胞。我们以前的工作也表明，神经营养因子BDNF介导了Nav1.6a活性依赖的信号。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交感神经节神经元以外的其他命运的可能性。在这里，我们提出了三个具体的目标，这将提供有关相关BDNF依赖信号转导的潜在机制的重要信息。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，我们确定了迁移性背根神经节神经元可能采用的全部细胞身份。目的3实验确定BDNF对分化的背根节神经元迁移表型的调控所依赖的基因表达变化。这一结果将提供可能导致治疗神经退行性疾病的替代策略的信息。

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.