Specification of Stochastic Left-Right Asymmetric Neuronal Fates in C. elegans

秀丽隐杆线虫随机左右不对称神经元命运的规范

• 批准号: 8539042
• 负责人: Chiou-Fen Chuang
• 金额: $ 28.05万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-31 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539042
• 关键词: Address; Animals; Applications Grants; Autistic Disorder; Biological Neural Networks; Biological Process; CCL4 gene; Caenorhabditis elegans; Calcium-Activated Potassium Channel; Cells; Communication; Complex; Connexins; Data; Defect; Development; Disease; Embryo; Epilepsy; Event; Future; Gap Junctions; Gene Expression Profile; Genes; Genetic; Genetic Screening; Goals; Homologous Gene; Human; Image; Individual; Left; Mediating; Microtubules; Modeling; Molecular; Mutation; Nervous system structure; Neurons; Odors; Organ; Pathway interactions; Peripheral Nervous System Diseases; Phenotype; Play; Potassium Channel; Process; Proteins; Relative (related person); Role; Scaffolding Protein; Side; Signal Transduction; Specific qualifier value; Synapses; System; Testing; To specify; Vertebrates; cell type; developmental disease; gain of function; gene function; genome sequencing; in vivo; innovation; mutant; neurodevelopment; neuron development; new technology; novel therapeutics; repaired; research study; voltage

DESCRIPTION (provided by applicant): The human nervous system consists of thousands of cell types with distinct patterns of gene expression and functions. One general way to diversify neuronal subtypes is to specify different identities and functions of individual cell types through stochastic neuronal fate choices. However, the mechanisms that generate stochastic cellular diversity in the nervous system are only partly understood. The C. elegans left and right AWC olfactory neurons specify asymmetric subtypes through a stochastic, coordinated cell signaling event, which allows the animal to discriminate between different odors. We have identified that this stochastic cell fate choice is regulated through a transient, embryonic NSY-5/innexin gap junction neural network that antagonizes a downstream Ca2+-regulated pathway to establish long-lasting asymmetric AWC identities. The overall goal of this proposal is to use this system as a model to identify the molecular mechanisms by which gap junction-mediated transient signaling events coordinate long- term stochastic neuronal fate choice. In this grant proposal, we will test the hypothesis that intercellular Ca2+ signaling mediates communication between AWCs and non-AWCs in the nsy-5 neural network to coordinate stochastic AWC subtype choice (Aim 1), investigate the role of Ca2+-activated SLO K+ channels and newly identified MOK (modifier of K+ channel) molecules in AWC subtype choice (Aim 2), and identify the mechanisms that regulate the synaptic localization of the TIR-1/Sarm1 Ca2+ signaling scaffold protein for AWC subtype choice (Aim 3). The establishment of long-lasting neuronal subtypes by a transient gap junction-dependent cell network provides an innovative, robust, and simple system to elucidate the molecular mechanisms underlying the biological function of gap junction-mediated intercellular signaling in development in vivo, which is not readily feasible in vertebrates. As mutations in the human homologs of the genes we study are associated with a variety of developmental disorders, understanding normal functions of these genes in mechanistic detail will inform novel therapeutic strategies.

描述（由申请人提供）：人类神经系统由数千种具有不同基因表达和功能模式的细胞类型组成。使神经元亚型多样化的一种通用方法是通过以下方式指定单个细胞类型的不同身份和功能： 随机神经元命运选择。然而，在神经系统中产生随机细胞多样性的机制尚不完全清楚。线虫左右 AWC 嗅觉神经元通过随机、协调的细胞信号传导事件指定不对称亚型，这使得动物能够区分不同的气味。我们已经发现，这种随机细胞命运选择是通过短暂的胚胎 NSY-5/innexin 间隙连接神经网络来调节的，该神经网络拮抗下游 Ca2+ 调节途径，以建立持久的不对称 AWC 身份。该提案的总体目标是使用该系统作为模型来识别间隙连接介导的瞬时信号事件协调长期随机神经元命运选择的分子机制。在本资助提案中，我们将测试细胞间 Ca2+ 信号传导介导 nsy-5 神经网络中 AWC 和非 AWC 之间的通信以协调随机 AWC 亚型选择（目标 1）的假设，研究 Ca2+ 激活的 SLO K+ 通道和新识别的 MOK（K+ 通道修饰剂）分子在 AWC 亚型选择中的作用（目标 2），并确定 调节 TIR-1/Sarm1 Ca2+ 信号支架蛋白突触定位以选择 AWC 亚型的机制（目标 3）。通过瞬时间隙连接依赖性细胞网络建立持久的神经元亚型提供了一种创新、强大且简单的系统，以阐明间隙连接介导的细胞间信号传导在体内发育的生物学功能背后的分子机制，这在脊椎动物中并不容易实现。由于我们研究的基因的人类同源物的突变与多种发育障碍有关，因此详细了解这些基因的正常功能将为新的治疗策略提供信息。