Genetic Control of Schwann Cell Differentiation

雪旺细胞分化的遗传控制

• 批准号: 7991793
• 负责人: JOHN Rutledge BERMINGHAM
• 金额: $ 35.26万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991793
• 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; 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; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Regulatory Pathway; Research Personnel; Role; Schwann Cells; Signal Pathway; Signal Transduction; Staging; Testing; Transgenic Mice; extracellular; mRNA Expression; mortality; myelination; nerve injury; novel strategies; overexpression; programs; protein expression; regenerative therapy; research study; response; sciatic nerve; segregation; transcription factor Oct-6

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.

项目摘要：髓鞘是脊椎动物神经系统的重要组成部分。都是再生性的 对脱髓鞘疾病的治疗和治疗将通过了解以下机制来促进 控制它的合成。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。在三叉神经核，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， 这是及时形成髓鞘所必需的。在爪爪突变小鼠中，轴突束的分离 雪旺细胞及其OCT-6下游效应基因的表达延迟，即使OCT-6是 正常激活。最近，我们发现爪爪突变的基因缺陷是一种 插入Lgi4(富含亮氨酸的胶质瘤灭活-4)基因。该基因由雪旺细胞表达，并且 编码一种功能未知的分泌蛋白。因此，雪旺细胞分泌一种它们需要的蛋白质 轴突分离，Oct-6靶基因的激活，以及髓鞘形成。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。 我们提出了以下目标来确定Lgi4在雪旺细胞发育中的作用：1)测试 认为雪旺细胞分化受Lgi4表达水平的调控。2)测试 假设Lgi4控制雪旺细胞必需基因的表达。3)检验假设 Lgi4通过Akt/PKB信号通路发挥作用。上面总结的实验侧重于识别 雪旺细胞对Lgi4介导的细胞外信号做出反应的信号通路；在这样做的过程中，我们将 阐明导致外周髓鞘形成的遗传调控途径，从而提供 为治疗髓鞘形成障碍的新疗法奠定了基础。 相关性：影响髓鞘的疾病，如中枢神经系统多发性硬化症，以及 周围神经系统中的遗传性脱髓鞘神经病，不仅使人虚弱，而且经常发生。通过 了解Lgi4蛋白如何控制雪旺细胞发育，我们将建立新的途径 髓鞘疾病和神经损伤的治疗。

项目成果

LGI proteins in the nervous system.

• DOI: 10.1042/an20120095
• 发表时间: 2013-06-25
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Kegel L;Aunin E;Meijer D;Bermingham JR
• 通讯作者: Bermingham JR

Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.

• DOI: 10.1523/jneurosci.6287-09.2010
• 发表时间: 2010-03-10
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ozkaynak E;Abello G;Jaegle M;van Berge L;Hamer D;Kegel L;Driegen S;Sagane K;Bermingham JR Jr;Meijer D
• 通讯作者: Meijer D