Regulation of Myelination by Egr2/Nab Protein Complexes

描述（由申请人提供）：Egr 2缺陷小鼠具有髓鞘化不足的外周神经的发现导致认识到EGFR 2是雪旺细胞髓鞘形成程序的重要调节剂，此外，还鉴定了遗传性神经病患者中的EGFR 2突变。这些患者中的突变型EGFR 2通过作为正常EGFR 2介导的髓鞘蛋白表达的显性抑制剂而引起髓鞘病。进一步的研究表明，NAB蛋白，与EGFR 2相互作用，并调节其转录活性，也是必要的周围神经髓鞘。总之，这些观察使我们假设EGR/NAB复合物是髓鞘形成的主要调节剂。使用培养的雪旺细胞，或来自髓鞘发育不足的小鼠突变体和发育中的小鼠的坐骨神经，或来自横断或压碎的坐骨神经的远端节段的表达谱实验已经能够鉴定“髓鞘形成相关基因簇”。该簇中基因的表达与髓鞘蛋白的表达密切相关，推断它们也参与髓鞘形成过程并受相同的转录调节因子调节，我们认为这些转录调节因子包括EGR/NAB复合物。在这里，我们概述了旨在确定由这些复合物调控的遗传网络的实验，这些遗传网络在髓鞘形成的许旺细胞中具有重要的功能。在通过表达谱鉴定候选靶基因后，现在将使用比较基因组分析和染色质免疫沉淀实验来鉴定EGR 2/NAB复合物结合的基因组位点。我们的表达谱分析还揭示了一种新的转录本，其在许旺细胞中的表达受EGR 2/NAB复合物的调控，并且与髓鞘蛋白的表达一致，并且其基因组位点与CMT神经病变位点紧密相连。将研究由该转录本编码的MP 11蛋白的功能。最后，我们将确定EGR 2是否是必要的和足够的介导的轴突信号，指导雪旺细胞激活髓鞘形成程序。

DESCRIPTION (provided by applicant): The discovery that Egr2-deficient mice have hypomyelinated peripheral nerves led to the realization that EGR2 is an essential regulator of the Schwann cell myelination program and, moreover, to the identification of EGR2 mutations in patients with inherited neuropathy. The mutant EGR2 in these patients causes myelinopathy by acting as a dominant inhibitor of the normal EGR2-mediated expression of myelin proteins. Further study demonstrated that NAB proteins, which interact with EGR2 and modulate its transcriptional activity, are also necessary for peripheral nerve myelination. Together, these observations have led us to hypothesize that EGR/NAB complexes are the prime regulators of myelination. Expression profiling experiments using cultured Schwann cells, or sciatic nerves from hypomyelinated mouse mutants and developing mice, or distal segments from transected or crushed sciatic nerves has enabled the identification of a 'myelination-associated gene cluster'. The expression of genes in this cluster is tightly correlated with that of myelin proteins, inferring that they are also involved in the myelination process and regulated by the same transcriptional regulators, which we believe include EGR/NAB complexes. Here, we have outlined experiments aimed at identifying the genetic networks that are regulated by these complexes and are functionally important in myelinating Schwann cells. Having identified candidate target genes by expression profiling, comparative genomic analysis and chromatin immunoprecipitation experiments will now be used to identify genomic loci where EGR2/NAB complexes are bound. Our expression profiling analyses also revealed a novel transcript whose expression in Schwann cells is regulated by EGR2/NAB complexes and is concordant with that of myelin proteins, and whose genomic loci is tightly linked with a CMT neuropathy locus. The function of the MP11 protein encoded by this transcript will be investigated. Finally, we will determine whether EGR2 is necessary and sufficient to mediate the axonal signals that direct Schwann cells to activate the myelination program.