Abstract
Mutations that disrupt Egr2 transcriptional activity cause severe demyelinating peripheral neuropathies. Here we provide evidence that Nab1 and Nab2 proteins are critical transcriptional modulators of Egr2 in myelinating Schwann cells. Like Egr2, these proteins are essential for Schwann cell differentiation into the myelinating state. Mice lacking both Nab1 and Nab2 show severe congenital hypomyelination of peripheral nerves, with Schwann cell development arresting at the promyelinating stage, despite elevated Egr2 expression. As observed for Egr2, Nab proteins are necessary for Schwann cells to exit the cell cycle, downregulate suppressed cAMP-inducible protein (SCIP) expression and upregulate expression of critical myelination genes. The mRNA expression signature of Schwann cells deficient in both Nab1 and Nab2 is highly similar to that of Egr2-deficient Schwann cells, further indicating that the Egr2/Nab protein complex is a key regulator of the Schwann cell myelination program and that disruption of this transcriptional complex is likely to result in Schwann cell dysfunction in patients with Egr2 mutations.
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Acknowledgements
We thank T. Gorodinsky, N. Panchenko and A. Nielson for technical assistance and members of the Milbrandt lab for comments on the manuscript. We thank members of the Siteman Cancer Center Bioinformatics Core for assistance in microarray analysis. We thank the laboratory of C. Semenkovich (NIH P60 DK20579) for assistance in bone densitometry analysis. This work was supported by US National Institutes of Health (NIH) grants NS4074 (J.M.), NIH R37 DK19645 (R.E.S.) and R01 AG10299 (R.E.S.).
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Supplementary information
Supplementary Fig. 1
Consensus Egr2 binding sites in Nab1 and Nab2 promoters. (PDF 2532 kb)
Supplementary Fig. 2
Nab1−/−Nab2−/− and Egr2Lo/Lo SCs have broadly overlapping expression profiles. (PDF 988 kb)
Supplementary Table 1
Genes disregulated in both Nab1−/−Nab2−/− and Egr2Lo/Lo nerves. (PDF 97 kb)
Supplementary Table 2
Genes disregulated specifically in Nab1−/−Nab2−/− nerves. (PDF 62 kb)
Supplementary Table 3
Genes disregulated specifically in Egr2Lo/Lo nerves. (PDF 60 kb)
Supplementary Table 4
Genes overexpressed by the Egr2(I268N) mutant. (PDF 54 kb)
Supplementary Table 5
Primer sequences for qRT-PCR. (PDF 39 kb)
Supplementary Video 1
Nab1−/−Nab2−/− mice are runted and display labored breathing, weakness, uncoordination and tremors. This video illustrates the behavior of a representative P14 Nab1−/−Nab2−/− mouse. (MOV 2529 kb)
Supplementary Video 2
Nab1−/−Nab2−/− and Egr2Lo/Lo mice display similar phenotypes. This video demonstrates the similar appearance and behavior (tremors) of age-matched P14 Nab1−/−Nab2−/− (left) and Egr2Lo/Lo (right) mice. (MOV 2812 kb)
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Le, N., Nagarajan, R., Wang, J. et al. Nab proteins are essential for peripheral nervous system myelination. Nat Neurosci 8, 932–940 (2005). https://doi.org/10.1038/nn1490
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DOI: https://doi.org/10.1038/nn1490
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