Genetic control of myelination by EGR2 and NAB proteins

描述（由申请人提供）：隔离 周围神经纤维对于神经信号的有效传导至关重要 通过运动和感觉神经。髓鞘是由雪旺氏细胞产生的， 这是一个由他们与发展中国家的联系引发的发展过程。 轴突几种周围神经病-包括腓骨肌萎缩症 (CMT)、Dejerine-Sottas综合征（DSS）和先天性髓鞘形成不足 神经病（CHN）-由髓磷脂形成和维持的缺陷引起， 并且编码EGR2反式激活因子的基因中的突变最近被 与这些疾病有关。这些结果证实了以前的工作， EGR2/Krox-20是小鼠髓鞘形成的关键调节因子， 发展 本申请的目的是阐明转录的机制， 在与EGR2相关的周围神经疾病中改变的控制 突变。几种神经病相关突变抑制EGR2与DNA的结合， 但所有这些突变都是显性的这一发现令人惊讶，因为只有 EGR2/Krox-20的一个功能性等位基因足以在神经胶质瘤中形成髓鞘。 小鼠为了了解显性突变体导致 周围神经病变，微阵列分析将用于识别基因 通过显性EGR2突变体的表达而变得失调。证据 表明显性突变体有效地隔离了一个关键的辅因子， EGR2活性和蛋白质-蛋白质相互作用的研究将被用于 识别这个辅助因子。最后，EGR2突变之一改变了一个结构域， 与NAB家族的辅阻遏物/辅激活蛋白相互作用。这 因此，隐性突变强烈暗示NAB蛋白是重要的 髓鞘形成的调节因子，微阵列分析将再次用于 研究NAB蛋白如何修饰EGR2基因网络的表达。 最后，显性负性NAB蛋白的表达将用于 研究NAB蛋白在外周神经髓鞘形成中的功能作用。 神经

DESCRIPTION (provided by the applicant): The myelin sheath that insulates peripheral nerve fibers is critical for efficient conduction of nerve signals through motor and sensory nerves. Myelin is produced by Schwann cells in a developmental process that is triggered by their association with developing axons. Several peripheral neuropathies-including Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN}-are caused by deficits in myelin formation and maintenance, and mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases. These results confirm previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The goal of this application is to elucidate the mechanisms of transcriptional control that become altered in peripheral nerve diseases associated with EGR2 mutations. Several neuropathy-associated mutations inhibit DNA-binding by EGR2, but all of these mutations are dominant. This finding is surprising since only one functional allele of EGR2/Krox-20 is sufficient for myelin formation in mice. To understand the mechanism by which the dominant mutants cause peripheral neuropathies, microarray analysis will be used to identify genes that become deregulated by expression of dominant EGR2 mutants. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions will be employed to identify this cofactor. Finally, one of the EGR2 mutations alters a domain that interacts with the NAB family of corepressor/coactivator proteins. This recessive mutation therefore strongly implicates the NAB proteins as important regulators of myelination, and microarray analysis will again be used to investigate how NAB proteins modify expression of the EGR2 gene network. Finally, expression of dominant negative NAB proteins will be used to investigate the functional role of NAB proteins in myelination of peripheral nerves.