Investigating the Role of cnb-1 and chpf-1 in GABA DD Motor Neuron Remodeling and Synapse Maintenance

研究 cnb-1 和 chpf-1 在 GABA DD 运动神经元重塑和突触维持中的作用

• 批准号: 10680262
• 负责人: Sam Liu
• 金额: $ 3.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-21 至 2026-03-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680262
• 关键词: Adolescent; Adult; Affect; Animals; Architecture; Axon; Birth; Brain; Caenorhabditis elegans; Calcineurin; Calcium; Calcium Signaling; Calcium-Binding Domain; Catalytic Domain; Cells; Cholinergic Receptors; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Dorsal; EF Hand Motifs; Engineering; Future; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Image; Intestines; Invertebrates; Label; Link; Maintenance; Masks; Modeling; Molecular; Motor Neurons; Muscle; Mutation; Nematoda; Nervous System; Neuroglia; Neurons; Operon; Pathway interactions; Phylogeny; Postembryonic; Presynaptic Terminals; Process; Proteasome Inhibitor; Proteins; Regulation; Role; Schizophrenia; Site; Supine Position; Synapses; Synaptic Receptors; Taxes; Techniques; Tissues; Transcriptional Regulation; Whole Organism; Work; autism spectrum disorder; calcineurin phosphatase; experimental study; gamma-Aminobutyric Acid; homeodomain; loss of function; multicatalytic endopeptidase complex; mutant; nervous system disorder; neural circuit; null mutation; postsynaptic; transcription factor; transcriptome sequencing

Project Summary During development of the human brain, synaptic connections undergo intensive rewiring in order to form mature circuits. Disruption of developmental remodeling in humans is linked to neurological disorders such as schizophrenia and autism spectrum disorders. The goal of this project is to identify conserved mechanisms that direct synapse remodeling. The ease of genetics, couple with the simpler organization and invariant architecture of invertebrate nervous systems offer strong advantages for studies of neuronal remodeling. My work focuses on the remodeling of GABAergic dorsal D-class (DD) motor neurons in the nemaode Caenorhabditis elegans. Prior studies have largely focused on the remodeling of presynaptic terminals. In contrast, my preliminary work has focused on understanding mechanisms that direct the elimination of postsynaptic receptors during remodeling. post-synaptic domain. The Francis lab previously demonstrated that the homeodomain transcription factor dve-1 is required for synapse elimination in GABA neurons. My work focuses on two putative DVE-1 targets, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory subunit of CalciNeurin PPP3R1/cnb-1, that were shown to be downregulated in dve-1 mutants. My preliminary studies suggest that mutation of either cnb-1 or chpf-1 disrupt synapse elimination during remodeling. My proposed work will determine the functional requirement and site of action for cnb-1, and identify the contribution of calcineurin phosphatase and proteasomal function to synapse elimination (Aim 1). In Aim 2, I will define how chpf-1 contributes to synapse elimination and maintenance. In Aim 3, I will identify additional potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will advance our understanding of remodeling and the mechanisms of regulation, potentially providing targets for future exploration.

项目摘要 在人脑的发展过程中，突触连接会进行密集的重新布线以形成 成熟的电路。人类发育重塑的破坏与神经系统疾病有关 精神分裂症和自闭症谱系障碍。该项目的目的是确定保守机制 直接突触重塑。遗传学的便利性，与更简单的组织和不变的夫妇 无脊椎动物神经系统的结构为神经元重塑的研究提供了强大的优势。我的 工作重点是Nemaode中GABA能背D级（DD）运动神经元的重塑 秀丽隐杆线虫。先前的研究主要集中在突触前末端的重塑上。在 对比，我的初步工作集中于理解指导消除的机制 重塑过程中突触后受体。突触后域。弗朗西斯实验室以前证明 同源域转录因子DVE-1是GABA神经元中消除突触所必需的。我的工作 专注于两个推定的DVE-1靶标，钙调神经蛋白样的EF手蛋白CHP1/CHPF-1和调节 钙调神经磷酸酶PPP3R1/CNB-1的亚基，这些亚基在DVE-1突变体中被下调。我的初步 研究表明，在重塑过程中，CNB-1或CHPF-1的突变破坏了突触消除。我的 拟议的工作将确定CNB-1的功能要求和作用部位，并确定 钙调神经磷酸酶磷酸酶和蛋白酶体功能对消除突触的贡献（AIM 1）。在AIM 2中，我 将定义CHPF-1如何促进突触消除和维护。在AIM 3中，我将确定其他 通过使用神经元特异性RNA-seq，在重塑途径中DVE-1的潜在靶标。我建议的工作将 促进我们对重塑和监管机制的理解，有可能为 未来的探索。