Heparan Sulfate in Schwann Cell Development and Myelination

硫酸乙酰肝素在雪旺细胞发育和髓鞘形成中的作用

• 批准号: 8185308
• 负责人: YU YAMAGUCHI
• 金额: $ 39.85万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185308
• 关键词: Acetylglucosamine; Adhesives; Adult; Alleles; Axon; Binding; Biological; Biological Models; Brain; Cells; Clinical; Communication; Development; EXT1 gene; Embryo; Enzymes; Ephrin-A3; Event; Generations; Genes; Glucuronic Acids; Heparan Sulfate Biosynthesis; Heparan Sulfate Proteoglycan; Heparitin Sulfate; In Vitro; Knock-out; Knockout Mice; Laminin; Mediating; Molecular; Mus; Myelin; Myelin Sheath; Nervous system structure; Neural Crest Cell; Neuregulin 1; Neuregulins; Neuroglia; Neurons; Neuropathy; Oligodendroglia; Peripheral; Peripheral Nerves; Peripheral Nervous System; Physiological; Physiology; Play; Proliferating; Reporting; Research; Role; Schwann Cells; Science; Series; Signal Transduction; System; insight; migration; myelination; nervous system development; nestin protein; precursor cell; research study; response

Our study using a conditional knockout of EXT1, te gene encoding an enzyme essential for heparan sulfate biosynthesis, has demonstrated the crucial ole of heparan sulfate proteoglycans (HSPGs) in multiple CMS morphogenetic evets (Inatani et al., Science 302:1144-1146, 2003). Yet the role of HSPGs in the nervous system is not limited to the CNS. There is evidece that HSPGs also play critical roles in the development and physiology of the peripheral nervous systm (PNS) by mediating molecular communications between axons and gia cells. This Component will focus on the role of heparan sulfate and HSPGs in neuron-glia interactions using Schwann cell-axon interactio as a model system. Aim 1. Role of heparan sulfate in Schwann cell development: We have found that in ur EXT1 conditional knockout mice, the number of Schwann cells in peripheral nerves is greatly reduced. This suggests that HSPGs play a crucial role in the proliferation and/or migration of Schwann cells, the developmental events in which axon-derived factors and adhesive interactions with axons play significan roles. We will employ the EXT1 conditional knockout mice, cultures of Schwan cells, and neuregulin-1 knockout mice to investigate the role of HSPGs in Schwann cell development and their involvement in neuregulin-ErB signaling. Aim 2. Role of heparan sulfate in myelin formation and function: Molecules that bind SPGs, such as laminins and neuregulins, are known to play criticalroles in myelination, and our preliminary studies have demonstrated aberrant myelination in the EXT1 conditional knockout mice. There are also clinicl reports suggesting that HSPGs are involved in the development of neuropathies. In this aim, by enetic, cell biological, and physiological experiments, we will investigate the role of HSPGs in developmental and physiological aspects of PNS myelin ensheathment. Overall, this Component will generatenew insight into the function of HSPGs in various types of neuron-glia interactions. Furthermore, through a series of collaborative studies, we will explore new lines of research at the interface between Components, obtaining answers to important questions beyond the immediate reaches of each Component.

我们的研究使用了 EXT1 的条件敲除，EXT1 是编码硫酸乙酰肝素必需酶的基因 生物合成，已证明硫酸乙酰肝素蛋白聚糖 (HSPG) 在多种 CMS 中的关键作用 形态发生事件（Inatani 等人，Science 302：1144-1146，2003）。然而 HSPG 在神经系统中的作用 系统不限于CNS。有证据表明 HSPG 在发育中也发挥着关键作用 通过介导周围神经系统（PNS）之间的分子通讯来调节和生理学 轴突和 gia 细胞。该部分将重点关注硫酸乙酰肝素和 HSPG 在神经元胶质细胞中的作用 使用施万细胞轴突相互作用作为模型系统。目标 1. 硫酸乙酰肝素在 雪旺细胞发育：我们发现，在 EXT1 条件敲除小鼠中， 周围神经的雪旺细胞大大减少。这表明 HSPG 在 雪旺细胞的增殖和/或迁移，轴突衍生因子和 与轴突的粘附相互作用发挥着重要作用。我们将使用 EXT1 条件敲除小鼠， 培养雪旺细胞和纽兰格林-1 敲除小鼠以研究 HSPG 在雪旺细胞中的作用 发育及其参与神经调节蛋白-ErB 信号传导。目标 2. 硫酸乙酰肝素在髓磷脂中的作用 形成和功能：结合 SPG 的分子，例如层粘连蛋白和神经调节蛋白，已知发挥作用 在髓鞘形成中发挥关键作用，我们的初步研究表明 EXT1 中存在异常髓鞘形成 条件敲除小鼠。也有临床报告表明 HSPG 参与了 神经病的发展。为了这个目标，通过遗传学、细胞生物学和生理学实验，我们将 研究 HSPG 在 PNS 髓鞘发育和生理方面的作用。 总体而言，该组件将为 HSPG 在各种类型神经元胶质细胞中的功能提供新的见解 互动。此外，通过一系列合作研究，我们将探索新的研究方向 组件之间的接口，获得超越直接问题的重要问题的答案 每个组件的范围。