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在神经元和神经胶质细胞之间建立复杂的功能相互作用。 少突胶质细胞 (OL) 是中枢神经系统的髓鞘形成细胞，在快速跳跃神经中发挥着关键作用 因此，OL 在整个成人中枢神经系统中的均匀分布。 至关重要，但它们的创始人少突胶质细胞祖细胞 (OPC) 是从发育上受到限制而产生的 大脑和脊髓中的脑室区区域必须经历广泛且协调的迁移。 在适当地停止迁移之前，我们已经展示了它们的目标轴突的分化和髓鞘化。 OPCs 首次通过在脉管系统上迁移的方式在中枢神经系统中分布，并且需要预先形成 发育血管的支架作为其迁移的物理基质 (6, 7)。 脉管系统对于它们的分散至关重要，对于允许 OPC 分化和适当的 CNS 也同样重要 髓鞘形成是其适当和及时脱离的调节，我们确实已经证明了这一缺陷。 OPC 从脉管系统脱离会阻碍其分化，并且可能不利于血液的完整性 但是 OPC 血管周围的迁移是如何终止并与其分化相协调的呢？ 关于 OPC 在分化时从脉管系统脱离的调节尚不清楚。 这笔资助将 (1) 表明星形胶质细胞协调 OPC 血管周围迁移和发生的停止 通过介导 OPC 从脉管系统脱离来分化，从而允许随后的 OPC 通过将它们从成熟抑制性内皮生态位中释放来进行分化，这将表明 星形细胞 Sema3a/6a 对 OPC Plexin 的排斥是从血管中释放 OPC 的机制。 还 (2) 回答有关 OPC 成熟发展决策的机制的问题 或仍然是祖细胞，表明脉管系统是 OPC 命运的外在控制中的关键角色 CNS OPC 成人库的决策和确定。