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: 10618323
• 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/10618323
• 关键词: ADGR1 gene; Actins; Adhesions; Agonist; Attention; Axon; Bilateral; Binding; Biology; Biotinylation; Brain; Cell Communication; Cell Proliferation; Cells; Cellular Morphology; Cellular biology; Central Nervous System; 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; Glutaminase; Human; In Vitro; Injury; Laminin; Ligands; Mediating; Membrane; Microglia; Microgyria; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Natural regeneration; Nervous System; Nervous System Physiology; Neuroglia; Oligodendroglia; Optic Nerve; Pathway interactions; Pattern; Play; Polymers; Process; Proteins; Proteomics; Publishing; Role; 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; pharmacologic; 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 Our unpublished data provide tantalizing evidence that (1) pmOL GPR56 is required for F-actin formation; (2) deleting Gpr56specifically in pmOLs results in reduced myelination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，可绝缘、滋养和保护轴突 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 髓鞘。 OL遵循有序、清晰的发展模式，具有阶段性的功能。 OL 前体细胞（OPC）增殖。髓鞘形成前 OL (pmOL) 介导初始轴突鞘和 髓鞘 OL (mOL) 进行迭代轴突包裹。我们发表的工作表明，G 蛋白偶联受体 (GPCR) GPR56 通过介导 OPC 之间的三方信号传导来调节 OPC 增殖。 OPC GPR56、小胶质细胞来源的组织转谷氨酰胺酶和基质蛋白层粘连蛋白-111。有趣的是，单身 细胞 RNAseq 数据显示，在 OL 谱系中，GPR56 在 pmOL 阶段表达最高。我们的 未发表的数据提供了诱人的证据，证明 (1) pmOL GPR56 是 F-肌动蛋白形成所必需的； (2)特异性删除pmOLs中的Gpr56会导致胼胝体(CC)髓鞘形成减少；和（3） 缺乏 Gpr56 的 pmOL 无法在共培养的 Shiverer 小脑切片中形成髓磷脂。服用这些 综合所有数据，我们假设 GPR56 在 pmOL 中发挥作用，调节髓鞘形成前 OL 过程的肌动蛋白组织。该提案旨在检验这一假设，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 了解髓鞘形成的基本生物学，并有可能揭示治疗的新目标 促进与髓磷脂损伤有关的广泛神经系统疾病的修复。