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: 10805054
• 负责人: Xianhua Piao
• 金额: $ 6.14万
• 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/10805054
• 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 Our unpublished data provide tantalizing evidence that (1) pmOL GPR56 is required for F-actin formation; (2) deleting Gpr56specifically in pmOLs results in reduced myelination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.

髓鞘是由神经胶质细胞产生的多层膜，用于隔离、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遵循有序而鲜明的发展模式，具有特定的阶段功能。OL 前体细胞(OPC)增殖。髓鞘前OL(PmoL)介导初始轴突包膜和 髓鞘形成OL(MOL)进行反复轴突包裹。我们已发表的工作表明，G蛋白偶联受体(GPCRGPR56)通过介导OPC增殖的三方信号通路调节OPC的增殖 OPC GPR56，小胶质细胞来源的组织转谷氨酰胺酶，和基质蛋白LN-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：(1)F-肌动蛋白的形成需要pmolGPR56； (2)在pmols中特异性缺失Gpr56会导致老茧体髓鞘形成减少；及(3) 缺乏GPr56的PMOL不能在共培养的寒战小脑片中形成髓鞘。带上这些 综上所述，我们假设GPR56在PMOL中发挥作用，调节髓鞘形成前OL过程中的肌动蛋白组织。这一建议旨在检验这一假说，从而建立新的GPCR PmolF-肌动蛋白聚合和轴突包膜中的信号通路。我们的数据将增强 了解髓鞘形成的基本生物学，并可能揭示治疗的新靶点 促进各种神经疾病的修复，这些疾病涉及髓鞘损伤。

项目成果

GPR56 S4 variant is required for microglia-mediated synaptic pruning.

GPR56 S4 变体是小胶质细胞介导的突触修剪所必需的。

• DOI: 10.1002/glia.24293
• 发表时间: 2023
• 期刊: Glia
• 影响因子: 6.2
• 作者: Li,Tao;Luo,Rong;Schmidt,Rachael;D'Alessandro,Nicholas;Kishore,Priya;Zhu,Beika;Yu,Diankun;Piao,Xianhua
• 通讯作者: Piao,Xianhua

The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA.

• DOI: 10.1038/ncomms7122
• 发表时间: 2015-01-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ackerman SD;Garcia C;Piao X;Gutmann DH;Monk KR
• 通讯作者: Monk KR

Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains.

• DOI: 10.1016/j.neuron.2016.08.022
• 发表时间: 2016-09-21
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Salzman GS;Ackerman SD;Ding C;Koide A;Leon K;Luo R;Stoveken HM;Fernandez CG;Tall GG;Piao X;Monk KR;Koide S;Araç D
• 通讯作者: Araç D

The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development.

• DOI: 10.1038/ncomms7121
• 发表时间: 2015-01-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Giera S;Deng Y;Luo R;Ackerman SD;Mogha A;Monk KR;Ying Y;Jeong SJ;Makinodan M;Bialas AR;Chang BS;Stevens B;Corfas G;Piao X
• 通讯作者: Piao X