Genetic Control of Schwann Cell Differentiation

雪旺细胞分化的遗传控制

• 批准号: 7212690
• 负责人: JOHN Rutledge BERMINGHAM
• 金额: $ 35.98万
• 依托单位: MC LAUGHLIN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-05 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212690
• 关键词: Accounting; Affect; Axon; Cell Death; Cell Differentiation process; Cell Survival; Cells; Cellular biology; Claw; Coculture Techniques; Complement; Cues; Defect; Deletion Mutation; Demyelinating Diseases; Development; Disease; Extracellular Matrix; Fascicle; Foundations; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genetic; Glioma; Inherited; Knowledge; Leucine; Mediating; Messenger RNA; Morbidity - disease rate; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutation; Myelin; Nerve; Nervous system structure; Neuraxis; Neuropathy; POU Domain; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phenotype; Play; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Regulatory Pathway; Research Personnel; Role; Schwann Cells; Signal Pathway; Signal Transduction; Staging; Testing; Transgenic Mice; extracellular; human TYRP1 protein; mortality; myelination; nerve injury; novel strategies; programs; protein expression; research study; response; sciatic nerve; segregation; transcription factor Oct-6

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.

描述（由申请人提供）：项目概述：髓鞘是脊椎动物神经系统的重要组成部分。再生疗法和脱髓鞘疾病的治疗都将通过控制其合成的机制的知识来促进。这些疾病是常见的，并占相当大的发病率和死亡率。然而，髓鞘形成和髓鞘再生的调节知之甚少。在PNS中，雪旺细胞需要轴突接触以进行增殖、存活和表达转录因子Oct-6，这是及时髓鞘形成所需的。在爪爪突变小鼠中，即使Oct-6被正常激活，许旺细胞的轴突束分离及其Oct-6下游效应基因的表达也被延迟。最近，我们已经确定了遗传缺陷潜在的爪爪突变插入Lgi 4（亮氨酸丰富的胶质瘤失活-4）基因。该基因由许旺细胞表达，并编码未知功能的分泌蛋白。因此，许旺细胞分泌轴突分离、Oct-6靶基因激活和髓鞘形成所需的蛋白质。我们假设Lgi 4触发或修改轴突或细胞外基质信号，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Lgi 4如何在许旺细胞发育中起作用：1）测试许旺细胞分化受Lgi 4表达水平调节的假设。2)检验Lgi 4控制必需的雪旺细胞基因表达的假设。3)检验Lgi 4通过Akt/PKB信号通路起作用的假设。上述总结的实验集中于鉴定对Lgi 4介导的细胞外信号传导作出响应的许旺细胞信号传导途径;在这样做时，我们将阐明导致外周髓鞘形成的遗传调控途径，从而为治疗髓鞘形成障碍的新疗法提供基础。 相关性：影响髓鞘的疾病，如中枢神经系统中的多发性硬化症和周围神经系统中的遗传性脱髓鞘神经病，都是使人衰弱和频繁的。通过了解Lgi 4蛋白如何控制许旺细胞发育，我们将建立治疗髓鞘疾病和神经损伤的新途径。