Adhesion G Protein-Coupled Receptors in CNS Development and Regeneration

CNS 发育和再生中的粘附 G 蛋白偶联受体

• 批准号: 10417182
• 负责人: Xianhua Piao
• 金额: $ 58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417182
• 关键词: ADGR1 gene; Actins; Adhesions; Agonist; Attention; Axon; Bilateral; Binding; Biology; Biotinylation; Brain; Cell Communication; Cell Proliferation; Cells; Cellular Morphology; Cellular biology; Coculture Techniques; Corpus Callosum; Data; Defect; Demyelinating Diseases; Development; Disease; Expression Profiling; F-Actin; Failure; Family; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Human; In Vitro; Injury; Laminin; Ligands; Mediating; Membrane; Microglia; Microgyria; Modeling; Multiple Sclerosis; Myelin; Myelin Sheath; Natural regeneration; Nervous System Physiology; Nervous system structure; Neuraxis; Neuroglia; Oligodendroglia; Optic Nerve; Pathway interactions; Pattern; Pharmacology; Play; Process; Proliferating; Proteins; Proteomics; Publishing; Role; Shivering; Signal Pathway; Signal Transduction; Slice; Testing; Work; Zebrafish; antagonist; cellular development; design; in vivo; inhibitor; loss of function mutation; member; mouse model; myelination; nervous system development; nervous system disorder; new therapeutic target; novel; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; polymerization; precursor cell; progenitor; protein expression; remyelination; repaired; single-cell RNA sequencing; therapeutic target; transglutaminase 2

Myelin is the multilamellar membrane generated by glial cells that insulates, nourishes and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. OL follow an orderly and distinct developmental pattern with stage-specific functions. OL precursor cell (OPC) proliferate. Pre-myelinating OL (pmOL) mediate initial axon ensheathment and myelinating OL (mOL) carry out iterative axon wraps. Our published work demonstrates that G protein-coupled receptor (GPCR) GPR56 regulates OPC proliferation by mediating a tripartite signaling between OPC GPR56, microglia-derived tissue transglutaminase, and matrix protein laminin-111. Intriguingly, single cell RNAseq data reveals that, within the OL lineage, GPR56 is expressed highest at the pmOL stage. Our unpublished data provide tantalizing evidence that (1) pmOL GPR56 is required for F-actin formation; (2) deleting Gpr56specifically in pmOLs results in reduced myelination of the corpus callosum (CC); and (3) pmOLs lacking Gpr56 were unable to form myelin in co-cultured Shiverer cerebellar slices. Taking these data all together, we hypothesize that GPR56 functions in pmOLs to regulate actin organization of the pre-myelinating OL process. This proposal is designed to test this hypothesis, thus establishing novel GPCR signaling pathway in pmOL F-actin polymerization and axon ensheathment. Our data will enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in the wide spectrum of neurological diseases that implicate myelin damage.

髓磷脂是由神经胶质细胞产生的多层膜，其隔离、包裹和保护轴突 在脊椎动物的神经系统中。在中枢神经系统（CNS）中，少突胶质细胞（OL）形成神经元。 髓鞘组织学习遵循着一个有序而独特的发展模式，具有阶段性的功能。OL 前体细胞（OPC）增殖。髓鞘形成前OL（pmOL）介导初始轴突鞘化， 髓鞘形成OL（mOL）进行迭代轴突缠绕。我们发表的工作表明，G蛋白偶联受体（GPCR）GPR 56通过介导OPC增殖之间的三方信号转导， OPC GPR 56、小胶质细胞衍生的组织转氨酶和基质蛋白层粘连蛋白-111。有趣的是，单身 cell RNAseq数据揭示，在OL谱系内，GPR 56在pmOL阶段表达最高。我们 未发表的数据提供了诱人的证据：（1）pmOL GPR 56是F-肌动蛋白形成所必需的; (2)特异性缺失pmOL中的Gpr 56导致胼胝体（CC）的髓鞘形成减少;和（3） 缺乏Gpr 56的pmOL不能在共培养的Shiverer小脑切片中形成髓鞘。服用这些 综上所述，我们假设GPR 56在pmOL中起调节髓鞘形成前OL过程的肌动蛋白组织的作用。该提案旨在验证这一假设，从而建立新的GPCR pmOL F-肌动蛋白聚合和轴突鞘中的信号通路。我们的数据将增强 了解髓鞘形成的基础生物学，并可能揭示一个新的治疗靶点， 促进涉及髓鞘损伤的广泛神经系统疾病的修复。