Do unique homeobox gene codes define all neuron classes of the C. elegans nervous system?

独特的同源框基因代码是否定义了秀丽隐杆线虫神经系统的所有神经元类别？

• 批准号: 9981026
• 负责人: Molly Booth Reilly
• 金额: $ 4.55万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981026
• 关键词: Adopted; Adoption; Adult; Anatomy; Applications Grants; Binding; C-terminal; CRISPR/Cas technology; Caenorhabditis elegans; Candidate Disease Gene; Code; Communities; Development; Excision; Expression Profiling; Family; Gene Expression; Genes; Genetic; Genetic Transcription; Genome engineering; Glutamates; Homeobox; Homeobox Genes; Individual; Maintenance; Maps; Mediating; Mitotic; Modeling; Molecular; Mutation; Nervous system structure; Neurons; Neurosciences; Neurotransmitters; Nucleic Acid Regulatory Sequences; Proteins; Proxy; Reagent; Regulation; Reporter; Resolution; Resources; Role; Specific qualifier value; Testing; Time; base; cholinergic; gene function; gene therapy; homeodomain; human disease; mutant; novel; transcription factor

Project Summary Despite our progress characterizing the molecular mechanisms by which post-mitotic neurons adopt their terminal identity features, it remains unclear if there are any overarching themes in regulation of terminal nervous system specification. In this grant proposal, I aim to analyze the function of a family of candidate regulators throughout an entire nervous system. To do this, I make use of the relatively simple C. elegans nervous system, which consists of 302 neurons in 118 anatomically distinct neurons classes. The mechanisms of neuronal identity specification have been probed in C. elegans, where genetic mutant analysis has uncovered a host of transcriptional regulators, designated terminal selectors. These terminal selectors control neuron-specific features by binding to cis regulatory regions upstream of neuron-specific genes and regulating their transcription. Of the terminal selectors that have been identified, most are homeodomain (HD) transcription factors belonging to the homeobox gene family. The broad usage of homeobox genes suggests that HD transcription factors may have evolutionarily ancient roles in specifying the terminal identity of an ancestral neuron type and, thus, I hypothesize that HD transcription factors are required for specification of every neuron in the C. elegans nervous system. To test this hypothesis, I propose analyzing the expression of more than 50 homeobox genes at a single neuron resolution using reporter strains. Then, I aim to determine if those HD transcription factors act as terminal selectors in the adult nervous system by examining the effect of their mutation on adoption of neurotransmitter identity. Thus far, I have completed examination of 22 homeobox reporters and found 20 to be expressed in post-mitotic neurons of the adult nervous system. One of those genes, ceh-34, was found to be a terminal selector in all the neurons where it is expressed. These results suggest that the proposal will likely identify novel regulators of terminal identity specification, and elucidate broad themes in development of post-mitotic neurons.

项目摘要 尽管我们在表征有丝分裂后神经元采用它们的分子机制方面取得了进展 终末身份特征，目前尚不清楚在终末神经调节中是否有任何主导主题 系统规格。在这项拨款提案中，我的目标是分析一个候选监管者家族的功能 贯穿整个神经系统。为了做到这一点，我利用相对简单的线虫神经系统， 它由118个解剖上不同的神经元类别的302个神经元组成。神经元同一性的机制 规范已经在线虫中进行了探索，那里的基因突变分析已经发现了一系列 转录调节因子，指定的末端选择器。这些终末选择器控制神经元特异性 通过与神经元特异性基因上游的顺式调节区结合并调节其转录来实现其功能。 在已鉴定的末端选择子中，大多数是同源结构域(HD)转录因子，属于 同源异型盒基因家族。同源盒基因的广泛使用表明HD转录因子可能 在指定祖先神经元类型的终端身份方面具有进化上的古老角色，因此，我 假设线虫神经中每个神经元的指定都需要HD转录因子 系统。为了验证这一假设，我建议分析50多个同源异型盒基因的表达 使用报告菌株进行神经元解析。然后，我的目标是确定这些HD转录因子是否作为末端 通过检测其突变对神经递质采纳的影响来研究成人神经系统中的选择素 身份。到目前为止，我已经完成了对22个Homeobox记者的检查，发现有20个在 成人神经系统的有丝分裂后神经元。其中一个基因，CEH-34，被发现是一个末端 在表达它的所有神经元中都有选择器。这些结果表明，该提案很可能会识别出 终末身份规范的调节者，并阐明有丝分裂后神经元发育的广泛主题。