Genetic control of myelination by EGR2 and NAB proteins

描述(申请人提供)：绝缘的髓鞘 周围神经纤维是神经信号有效传导的关键 通过运动神经和感觉神经。髓鞘是由雪旺细胞在一种 由他们与发展中的联系触发的发展过程 轴突。几种周围神经病--包括夏科-玛丽-图斯病 先天性髓鞘低下症(CMT)、DeJerine-Sottas综合征(DSS) 神经病(CHN)-由髓鞘形成和维持缺陷引起， 编码EGR2反式激活因子的基因最近发生了突变 与这些疾病有关。这些结果证实了之前的工作表明 EGR2/KROX-20是小鼠髓鞘形成的关键调控因子 发展。 这项应用的目的是阐明转录的机制。 与EGR2相关的周围神经疾病中发生改变的控制 突变。一些与神经病变相关的突变抑制了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的一个功能等位基因足以促进髓鞘的形成 老鼠。为了了解显性突变体导致 周围神经疾病，微阵列分析将用于识别基因 被显性的EGR2突变体的表达所解除的调控。证据 表明显性突变体有效地隔离了关键的辅因子 EGR2活性和蛋白质-蛋白质相互作用的研究将被用于 找出这个辅因。最后，EGR2的一个突变改变了一个结构域， 与辅阻遏子/辅活化子蛋白的NAB家族相互作用。这 因此，隐性突变强烈地暗示NAB蛋白是重要的 髓鞘形成的调节剂和微阵列分析将再次用于 研究NAB蛋白如何改变EGR2基因网络的表达。 最后，显性负性NAB蛋白的表达将被用于 探讨NAB蛋白在外周血髓鞘形成中的功能作用 太紧张了。

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.