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ext1的有条件敲除，te基因编码硫酸乙酰肝素必不可少的酶 生物合成已经证明了多个CMS中硫酸乙酰肝素蛋白聚糖（HSPG）至关重要 形态发生的Evets（Inatani等人，Science 302：1144-1146，2003）。然而，HSPG在神经上的作用 系统不限于中枢神经系统。有人有Evidece HSPG在开发中也起着关键作用 通过介导分子通信之间的外周神经系统（PNS）的生理学 轴突和GIA细胞。该成分将重点介绍硫酸乙酰肝素和HSPG在神经元中的作用 使用Schwann Cell-Axon Interactio作为模型系统的交互。目的1。硫酸乙酰肝素的作用 Schwann细胞开发：我们发现在UR Ext1有条件敲除小鼠中，数量 周围神经中的雪旺细胞大大降低。这表明HSPG在 雪旺细胞的增殖和/或迁移，轴突衍生因素和 与轴突的粘合剂相互作用起着显着的作用。我们将采用Ext1条件敲除小鼠， 雪旺细胞的培养物和Neuregulin-1基因敲除小鼠研究HSPG在Schwann细胞中的作用 发育及其参与神经蛋白ERB信号传导。 AIM 2。硫酸乙酰肝素在髓鞘中的作用 形成和功能：已知结合SPG的分子，例如层粘连蛋白和神经结合蛋白 髓鞘中的关键物质以及我们的初步研究表明ext1中的髓鞘异常 有条件的淘汰小鼠。还有诊所的报告表明，HSPG参与了 神经病的发展。在此目标中，通过酸化，细胞生物学和生理实验，我们将 研究HSPG在PNS髓磷脂内部的发育和生理方面的作用。 总体而言，该组件将洞悉HSPG在各种类型的神经元中的功能 互动。此外，通过一系列协作研究，我们将探索新的研究线 组件之间的接口，从直接的 每个组件的范围。