Heparan Sulfate in Schwann Cell Development and Myelination

我们的研究使用了编码硫酸乙酰肝素必需的酶的EXT1，TE基因的条件性敲除 已证实在多种CMS中硫酸乙酰肝素蛋白多糖(HSPGs)的生物合成是关键 形态发生Evets(Inatani等人，Science 302：1144-1146,2003)。然而，热休克蛋白在神经细胞中的作用 系统并不局限于CNS。有证据表明，HSPG在发展中也发挥了关键作用 和周围神经系统(PNS)的生理学 轴突和Gia细胞。本部分将重点介绍硫酸乙酰肝素和热休克蛋白在神经胶质细胞中的作用。 以雪旺细胞-轴突相互作用为模型系统的相互作用。目的1.硫酸乙酰肝素在体内的作用 雪旺细胞发育：我们发现在ur EXT1条件性基因敲除小鼠中， 周围神经中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 与轴突的粘附性相互作用起着重要作用。我们将使用EXT1条件基因敲除小鼠， 培养雪旺细胞和NeuRegin-1基因敲除小鼠以研究HSPGs在雪旺细胞中的作用 神经调节蛋白-Erb信号转导机制的研究进展。目的2.硫酸乙酰肝素在髓鞘中的作用 形成和功能：结合SPG的分子，如层粘连蛋白和神经调节蛋白，已知在其中发挥作用 在髓鞘形成中的关键作用，我们的初步研究表明EXT1中存在异常的髓鞘形成 条件基因敲除小鼠。也有临床报告表明，HSPG参与了 神经疾病的发展。在这一目标中，通过遗传学、细胞生物学和生理学实验，我们将 研究HSPGs在三叉神经节髓鞘发育和生理方面的作用。 总体而言，这一部分将对HSPG在各种类型的神经元-胶质细胞中的功能产生新的见解 互动。此外，通过一系列合作研究，我们将探索新的研究路线， 组件之间的接口，获得即时之外的重要问题的答案 每个组件的覆盖范围。

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.