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: 9795693
• 负责人: Molly Booth Reilly
• 金额: $ 4.5万
• 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/9795693
• 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 尽管我们在有丝分裂后神经元接受其功能的分子机制方面取得了进展， 终末身份特征，目前还不清楚是否有任何支配性的主题，在调节终末神经元 系统规格在这份拨款申请中，我的目标是分析一系列候选监管机构的功能 在整个神经系统中。为了做到这一点，我使用了相对简单的C。线虫的神经系统， 其由118个解剖学上不同的神经元类中的302个神经元组成。神经元同一性的机制 规范进行了探讨。基因突变分析发现了许多 转录调节因子，指定为末端选择因子。这些终端选择器控制神经元特异性 其特征在于与神经元特异性基因上游的顺式调控区结合并调控其转录。 在已经鉴定的末端选择子中，大多数是同源域（HD）转录因子，其属于 同源异型盒基因家族同源异型盒基因的广泛使用表明HD转录因子可能 在确定祖先神经元类型的终端身份方面具有进化上古老的作用，因此， 假设HD转录因子是C.秀丽隐翅虫 系统为了验证这一假设，我建议分析50多个同源框基因的表达，在一个单一的 使用报告菌株的神经元分辨率。然后，我的目标是确定这些HD转录因子是否充当终端 通过检查其突变对神经递质通过的影响， 身份到目前为止，我已经完成了对22个同源框报告基因的检查，发现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，被发现是一个终端， 在所有表达它的神经元中的选择器。这些结果表明，该提案可能会发现新的 终端身份规范的监管机构，并阐明有丝分裂后神经元的发展的广泛主题。