Genetic Control of Schwann Cell Differentiation

描述(申请人提供)：项目摘要：髓鞘是脊椎动物神经系统的重要组成部分。通过了解控制其合成的机制，再生疗法和脱髓鞘疾病的治疗都将得到促进。这些疾病是常见的，占相当大的发病率和死亡率。然而，对髓鞘形成和再髓鞘形成的调控知之甚少。在三叉神经节，雪旺细胞需要轴突接触才能增殖、存活和转录因子Oct-6的表达，而OCT-6是及时髓鞘形成所必需的。在爪爪突变小鼠中，尽管Oct-6被正常激活，但雪旺细胞对轴突束的分离及其下游效应基因的表达都延迟了。最近，我们已经确定爪爪突变的遗传缺陷是插入了Lgi4(富含亮氨酸的胶质瘤失活-4)基因。该基因由雪旺细胞表达，编码一种功能未知的分泌性蛋白。因此，雪旺细胞分泌一种它们需要的蛋白质，用于轴突分离、OCT-6靶基因的激活和髓鞘形成。我们假设Lgi4触发或修饰轴突或细胞外基质信号(S)，从而调节雪旺细胞对这些信号的反应。我们提出了以下目的来确定Lgi4在雪旺细胞发育中的作用：1)检验雪旺细胞分化受Lgi4表达水平调控的假设。2)验证Lgi4控制雪旺细胞必需基因表达的假设。3)验证Lgi4通过Akt/PKB信号通路发挥作用的假设。以上总结的实验侧重于确定雪旺细胞对Lgi4介导的细胞外信号做出反应的信号通路；在此过程中，我们将阐明导致外周髓鞘形成的基因调控通路，从而为治疗髓鞘疾病的新疗法提供基础。 相关性：影响髓鞘的疾病，如中枢神经系统的多发性硬化症和周围神经系统的遗传性脱髓鞘神经病，都是衰弱和常见的。通过了解Lgi4蛋白如何控制雪旺细胞的发育，我们将建立治疗髓鞘疾病和神经损伤的新途径。

DESCRIPTION (provided by applicant): Project Summary: Myelin is a crucial component of vertebrate nervous systems. Both regenerative therapies and treatment of demyelinating diseases will be facilitated by knowledge of the mechanisms that control its synthesis. These diseases are frequent, and account for considerable morbidity and mortality. However, the regulation of myelination and remyelination is poorly understood. In the PNS, Schwann cells require axonal contact for proliferation, survival, and for the expression of the transcription factor Oct-6, which is required for timely myelination. In claw paw mutant mice, both the segregation of axon fascicles by Schwann cells and their expression of Oct-6 downstream effector genes is delayed, even though Oct-6 is activated normally. Recently, we have identified the genetic defect underlying the claw paw mutation as an insertion in the Lgi4 (Leucine-rich glioma inactivated-4) gene. This gene is expressed by Schwann cells, and encodes a secreted protein of unknown function. Thus Schwann cells secrete a protein that they require for axon segregation, activation of Oct-6 target genes, and myelination. We hypothesize that Lgi4 triggers or modifies axonal or extracellular matrix signal(s), thereby regulating Schwann cell responses to these cues. We propose the following aims to determine how Lgi4 functions in Schwann cell development: 1) Test the hypothesis that Schwann cell differentiation is modulated by the level of Lgi4 expression. 2) Test the hypothesis that Lgi4 controls the expression of essential Schwann cell genes. 3) Test the hypothesis that Lgi4 acts through the Akt/PKB signaling pathway. The experiments summarized above focus on identifying Schwann cell signaling pathways that respond to Lgi4-mediated extracellular signaling; in doing so, we will elucidate the genetic regulatory pathways that result in the formation of peripheral myelin, thereby providing the foundation for new therapies to treat myelination disorders. Relevance: Diseases that affect myelin, such as multiple sclerosis in the central nervous system, and inherited demyelinating neuropathies in the peripheral nervous system, are both debilitating and frequent. By understanding how the Lgi4 protein controls Schwann cell development, we will establish new avenues for the treatment of myelin disorders and nerve injury.