ROLE OF EGR2 MUTATIONS IN PERIPHERAL MYELINOPATHIES

描述(摘自申请者摘要)：遗传性神经病 人类最常见的遗传病。这些症状的特点是 神经髓鞘异常继发严重的运动和感觉障碍 导致严重的病人发病率和死亡率。潜在的 这些神经疾病的遗传缺陷主要发生在编码 髓鞘结构蛋白MPZ、PMP-22和连接蛋白-32。然而，最近， 转录因子Egr2的突变也与这些 综合症。Egr2与这些症状之间的联系是在 Egr2基因缺陷小鼠的外周神经出现有髓鞘不良 雪旺细胞分化停滞于早髓细胞期。一起， 这些结果有力地表明Egr2是一种重要的调节因子。 分化程序，最终形成髓鞘雪旺细胞 表型。在这项提案中，我们概述了旨在理解 Egr2调控髓鞘形成过程的分子机制。 用腺病毒感染雪旺细胞的功能获得实验将 可用于通过微阵列筛选进行Egr2靶基因谱分析。 与遗传性神经疾病相关的Egr2突变体将在 体外髓鞘形成试验并检测其激活表达的能力 Egr2靶基因。此外，一种与神经病变相关的Egr2 突变位于与NAB蛋白相互作用的区域， Egr2活性的调节剂。因此，我们将调查NAB的角色 调节髓鞘形成的蛋白质。Nabl或Nabl基因突变的存在 遗传性神经病患者将寻找NaB2基因。最后，基因 靶向将被用于培育出携带神经病变相关Egr2的小鼠 突变，以创造这些遗传性神经疾病的小鼠模型。这个 将检查这些小鼠的周围神经系统是否存在缺陷 雪旺细胞分化与周围神经髓鞘形成。表达方式 将在这些突变小鼠的神经中检测Egr2调节基因的部分。这些 研究将为Egr2基因突变如何导致外周血细胞病变提供新的见解 神经疾病，可能导致这些疾病的新疗法的信息。

DESCRIPTION (From the Applicant's Abstract): Inherited neuropathies are among the most common human genetic diseases. These syndromes are characterized by severe motor and sensory deficits secondary to abnormal nerve myelination resulting in significant patient morbidity and mortality. The underlying genetic defects of these neuropathies occur primarily in genes encoding the myelin structural proteins MPZ, PMP-22 and connexin-32. Recently, however, mutations in the transcription factor Egr2 have also been associated with these syndromes. The connection between Egr2 and these syndromes was made after peripheral nerves in Egr2-deficient mice appeared poorly myelinated due to a Schwann cell differentiation arrest at the promyelinating stage. Together, these results strongly suggest that Egr2 is a crucial regulator of a differentiation program, which culminates in the myelinating Schwann cell phenotype. In this proposal, we outline experiments aimed at understanding the molecular mechanisms by which Egr2 regulates the myelination process. Gain-of-function experiments using adenovirus infection of Schwann cells will be utilized to perform Egr2 target gene profiling via microarray screening. Egr2 mutants associated with inherited neuropathies will be characterized in in vitro myelination assays and tested for their ability to activate expression of Egr2 target genes. In addition, one of the neuropathy-associated Egr2 mutations is located in the domain that interacts with the Nab proteins, modulators of Egr2 activity. We will therefore investigate the role of the Nab proteins in regulating myelination. The presence of mutations in the Nabl or Nab2 genes will be sought in patients with inherited neuropathy. Finally, gene targeting will be used to produce mice that harbor neuropathy-associated Egr2 mutations in order to create mouse models of these inherited neuropathies. The peripheral nervous system of these mice will be examined for deficits in Schwann cell differentiation and peripheral nerve myelination. The expression of Egr2-regulated genes will be examined in nerves of these mutant mice. These studies will provide new insight into how mutations in Egr2 lead to peripheral neuropathies, information that may lead to novel therapies for these diseases.