Heparan Sulfate in Schwann Cell Development and Myelination

我们的研究使用条件敲除EXT 1，te基因编码硫酸乙酰肝素必需的酶 硫酸乙酰肝素蛋白聚糖（HSPG）在多种CMS生物合成中的重要作用 形态发生学evets（Inatani等，Science 302：1144-1146，2003）。然而，HSPGs在神经系统中的作用 系统不限于CNS。有证据表明，HSPG在发展中也发挥着关键作用， 和生理学的周围神经系统（PNS）通过介导分子之间的通信 轴突和GIA细胞。本部分将重点讨论硫酸乙酰肝素和HSPGs在神经胶质细胞中的作用 使用Schwann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：我们发现在我们的EXT 1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在这一过程中起着至关重要的作用。 雪旺细胞的增殖和/或迁移，其中轴突衍生因子和 与轴突的粘附相互作用起重要作用。我们将使用EXT 1条件性敲除小鼠， 培养的雪旺细胞和neuregulin-1基因敲除小鼠，以研究HSPGs在雪旺细胞中的作用。 发育和参与神经调节蛋白-ErB信号传导。目标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，如层粘连蛋白和神经调节蛋白， 在髓鞘形成中起着关键作用，我们的初步研究已经证明了EXT 1中的异常髓鞘形成。 条件性基因敲除小鼠也有临床报告表明，HSPG参与了 神经病变的发展。为此，通过遗传学、细胞生物学和生理学实验， 研究HSPGs在PNS髓鞘形成的发育和生理方面的作用。 总的来说，这一组件将产生新的见解，在各种类型的神经胶质细胞的功能HSPGs 交互.此外，通过一系列的合作研究，我们将探索新的研究领域， 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.