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: 8371500
• 负责人: Chiou-Fen Chuang
• 金额: $ 29.07万
• 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/8371500
• 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. PUBLIC HEALTH RELEVANCE: Developmental disorders asociated with defects in neuronal development cause enormous human suffering. Since stochastic cell fate acquisition and gap junction- mediated signaling are two conserved and central problems in neural development, understanding mechanisms of stochastic cellular diversity and gap junction function in the nervous system may elucidate the disease processes resulting from early defects in these events and provide models for their eventual repair. The proteins (gap junctions, voltage-activated Ca2+ chanels, Ca2+-activated K+ chanels, and the TIR-1/Sarm1 scaffold protein) we study are conserved and widely distributed in the vertebrate nervous system and many other organs, and mutations in the human homologs of these genes are associated with a variety of developmental disorders such as peripheral neuropathy, autism, and epilepsy. Thus, a better understanding of normal functions of these genes in mechanistic detail will inform novel therapeutic strategies.

描述(申请人提供)：人类神经系统由数千种不同类型的细胞组成，具有不同的基因表达和功能模式。使神经元亚型多样化的一种普遍方法是通过 随机的神经元命运选择。然而，在神经系统中产生随机细胞多样性的机制只被部分了解。线虫左侧和右侧AWC嗅觉神经元通过随机、协调的细胞信号事件指定不对称亚型，这使动物能够区分不同的气味。我们已经证实，这种随机的细胞命运选择是通过一个瞬时的胚胎NSY-5/innexin缝隙连接神经网络来调节的，该神经网络拮抗下游的钙离子调节途径，建立长期的不对称AWC身份。这一建议的总体目标是将该系统作为一个模型来识别缝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。在这项拨款计划中，我们将在NSY-5神经网络中验证细胞间钙信号介导AWC和非AwC之间的通信的假设，以协调AWC亚型选择(目标1)，研究钙激活的SLO K+通道和新发现的K+通道修饰物(MOK)分子在AWC亚型选择中的作用(目标2)，并确定调节AWC亚型选择的TIR-1/Sarm1钙+信号支架蛋白突触定位的机制(目标3)。通过瞬时缝隙连接依赖的细胞网络建立长时间神经元亚型提供了一个创新的、健壮的和简单的系统来阐明缝隙连接介导的细胞间信号在体内发育中潜在的生物学功能的分子机制，这在脊椎动物中是不容易实现的。由于我们研究的基因在人类同源基因中的突变与各种发育障碍有关，了解这些基因的机械细节的正常功能将为新的治疗策略提供信息。 公共卫生相关性：与神经元发育缺陷相关的发育障碍会给人类带来巨大的痛苦。由于细胞命运的随机获得和缝隙连接介导的信号传导是神经发育中的两个保守而核心的问题，了解神经系统中随机细胞多样性和缝隙连接功能的机制可能会阐明这些事件早期缺陷导致的疾病过程，并为最终的修复提供模型。我们研究的蛋白质(缝隙连接、电压激活的钙通道、钙激活的K+通道和TIR-1/Sarm1支架蛋白)在脊椎动物的神经系统和许多其他器官中都是保守的，并且广泛分布，这些基因在人类同源基因中的突变与各种发育障碍有关，如周围神经病、自闭症和癫痫。因此，更好地了解这些基因在机制细节上的正常功能将为新的治疗策略提供信息。