Astrocytes control the termination of oligodendrocyte precursor cell perivascular migration during CNS development

星形胶质细胞控制中枢神经系统发育过程中少突胶质细胞前体细胞血管周围迁移的终止

• 批准号: 10727537
• 负责人: Stephen Philip James Fancy
• 金额: $ 44.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727537
• 关键词: AMD3100; Ablation; Acute; Adult; Affect; Astrocytes; Axon; Blood - brain barrier anatomy; Blood Vessels; Brain; CSPG4 gene; Cell Differentiation process; Cells; Cytomegalovirus; Data; Development; Diphtheria Toxin; Dose; Embryo; Endothelium; Grant; Human; Image; In Vitro; Label; Lasers; Lectin; LoxP-flanked allele; Mediating; Membrane Proteins; Molecular; Mus; Neural Conduction; Neuroglia; Neurons; Oligodendroglia; Pericytes; Platelet-Derived Growth Factor alpha Receptor; Process; Proteomics; Regulation; Reporter Genes; Role; Semaphorin-3A; Semaphorins; Slice; Spinal Cord; Stains; Tamoxifen; Time; Tissues; Transgenic Organisms; Ventricular; Visualization; antagonist; comparison control; in vivo; knock-down; migration; myelination; offspring; oligodendrocyte precursor; oligodendrocyte progenitor; overexpression; plexin; postnatal; postnatal development; precursor cell; progenitor; scaffold; spatiotemporal; stem cells

PROJECT ABSTRACT: The adult mammalian CNS requires establishment of intricate functional interactions between neurons and glia. Oligodendrocytes (OL), the myelinating cells of the CNS, have critical roles in allowing for rapid saltatory nerve conduction and in maintaining axon integrity. The uniform distribution of OL throughout the adult CNS is therefore critical, but their founder oligodendrocyte progenitor cells (OPCs) arise developmentally from restricted ventricular zone domains in brain and spinal cord. OPCs must undergo an extensive and coordinated migration before halting migration appropriately to differentiate and myelinate their target axons. We have shown for the first time that OPCs distribute through the CNS by migrating on the vasculature, and require the pre-formed scaffold of developed blood vessels as their physical substrate for migration (6, 7). Whilst OPC association with vasculature is critical for their dispersal, equally important for permitting OPC differentiation and proper CNS myelination is the regulation of their appropriate and timely detachment. Indeed we have shown that defective OPC detachment from vasculature blocks their differentiation and can be detrimental to the integrity of the blood brain barrier (8). But how is OPC perivascular migration terminated and co-ordinated with their differentiation? Nothing is known about the regulation of OPC detachment from vasculature at the time of their differentiation. This grant will (1) show that astrocytes co-ordinate the halting of OPC perivascular migration and onset of differentiation by mediating OPC detachment from vasculature, allowing for subsequent OPC differentiation by releasing them from a maturation inhibitory endothelial niche. It will show that an astrocytic Sema3a/6a to OPC Plexin repulsion is the mechanism for releasing OPCs from vessels. It will also (2) answer questions about the mechanisms underlying an OPC’s developmental decision to mature or remain a progenitor, showing that the vasculature is a key player in the extrinsic control of OPC fate decisions and determination of an adult pool of CNS OPCs.

项目摘要： 成年哺乳动物中枢神经系统需要建立神经元与神经胶质之间的复杂功能相互作用。 少突胶质细胞（OL），CNS的髓鞘细胞，在允许快速盐神经方面具有关键作用 传导和维持轴突完整性。因此，OL在整个成人中枢神经系统中的均匀分布是 关键，但其创始人的少突胶质细胞祖细胞（OPC）是由受限制的 大脑和脊髓中的心室区域。 OPC必须进行广泛而协调的迁移 在适当地停止迁移以区分和髓鞘的靶轴突之前。我们已经显示了 OPC通过在脉管系统上迁移的第一次通过中枢神经系统分发，并需要预先形成的 发达的血管作为迁移的物理基质的脚手架（6，7）。而OPC与 脉管系统对它们的扩散至关重要，对于允许OPC分化和适当的CNS同样重要 髓鞘化是对它们适当及时的分离的调节。确实，我们已经证明了有缺陷的 OPC脱离脉管系统会阻止其分化，并可能不利于血液的完整性 脑屏障（8）。但是，OPC周围迁移如何与它们的分化终止和协调？ 关于OPC分化时对脉管系统的调节，对OPC脱离的调节一无所知。 该赠款将（1）表明星形胶质细胞协调OPC周围迁移和发作的停止 通过介导OPC脱离脉管系统来分化，从而允许随后的OPC 通过释放出成熟的抑制性内皮细分市场来分化。它将表明 星形胶质细胞SEMA3A/6A至OPC丛集抑制是从血管中释放OPC的机制。会 还（2）回答有关OPC成熟决定的机制的问题 或保持祖先，表明脉管系统是OPC命运外部控制的关键参与者 CNS OPC的成人库的决策和确定。