Analysis of EGR2-driven microRNAs in Schwann cells

Purpose: The goal of this study is to identify EGR2-driven microRNAs that promote myelination in Schwann cells. Background: Charcot-Marie-Tooth disease can be caused by mutations in Early Growth Response 2 (EGR2) gene. EGR2 is the master regulator of myelination in Schwann cells. It not only activates many genes involved in myelin formation and maintenance, but also represses several genes characteristic of the immature stage to promote differentiation. We hypothesized that EGR2 represses antecedent gene programs, in part, through microRNA-mediated repression. Such EGR2-driven microRNAs, if exist, may be used to treat patients with demyelinating neuropathies. Methods: We look for microRNA candidates that are 1) developmentally upregulated in Schwann cells, 2) downregulated in mice with congenital hypomyelination phenotype, 3) predicted bioinformatically to target negative regulators of myelination, including Sox2, Jun and Notch1, 4) downregulated in crushed nerves, and 5) induced by the master regulator Egr2. Results: Our results show that miR-138 is robustly upregulated in Schwann cells during development, drastically reduced in the Dicer1 cKO and Dgcr8 cKO mice, bioinformatically predicted to target the genes that negatively regulate myelination, downregulated in injured nerves, and significantly low in Egr2-null mice. We have also shown that EGR2 and SOX10 bind directly to an active enhancer near mir-138-1 locus and the upregulation of miR-138 during development is EGR2-dependent. Conclusions: We have identified miR-138 as an EGR2-driven microRNA that may promote myelination in Schwann cells. Next step will be to validate our findings through in vivo loss-of-functions and gain-of-function experiments. This work was supported by National Institutes of Health Grants 1R01NS071081-01.