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神经元和神经胶质之间建立复杂的功能相互作用。 少突胶质细胞（OL），中枢神经系统的髓鞘细胞，具有关键作用，使快速跳跃神经 传导和维持轴突完整性。因此，OL在整个成人CNS中的均匀分布是 关键的，但他们的创始人少突胶质细胞祖细胞（OPCs）出现发展从限制 脑和脊髓中的脑室区域。OPC必须经历广泛和协调的迁移 然后适当地停止迁移以分化和髓鞘化它们的靶轴突。我们已经展示了 OPCs首次通过在血管系统上迁移而分布通过CNS，并且需要预形成的 发达血管的支架作为迁移的物理基质（6，7）。虽然OPC与 血管对于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。 髓鞘形成是它们适当和及时脱离的调节。事实上，我们已经证明， OPC从脉管系统中分离会阻碍它们的分化，并可能对血液的完整性有害 脑屏障（8）。但是，OPC血管周围迁移是如何终止的，并与它们的分化相协调？ 目前还不清楚OPC在分化时从脉管系统中脱离的调控。 这项资助将（1）显示星形胶质细胞协调OPC血管周围迁移和发病的停止 通过介导OPC从血管系统中分离， 通过将它们从成熟抑制内皮小生境释放来分化。它将表明， 星形胶质细胞Sema 3a/6a对OPC丛蛋白的排斥是从血管释放OPC的机制。它将 还（2）回答有关OPC发育决定成熟的机制的问题 或保持为祖细胞，表明血管系统在OPC命运的外在控制中起关键作用 决定和确定成年CNS OPC库。