Our laboratory is focused on the transcriptional and epigenetic regulation of myelination. Myelin is a vital constituent of the nervous system that increases the speed of action potentials, and also provides trophic support for the long axons that project from neurons. Our studies are centered on the myelin-producing cells of the peripheral nervous system, and the picture below shows a Schwann cell that has synthesized a myelin sheath around the axon to the left. We have focused on elucidating gene regulation of individual myelin genes by two major regulators of Schwann cell function: Egr2 and Sox10. Sox10 is required at virtually all phases of Schwann cell development and Egr2 is required for initation of myelination. For example, we have recently characterized enhancers within the Pmp22 gene, which is duplicated in the most common form of Charcot-Marie-Tooth Disease, classified as CMT1A. These studies are also developing novel screening assays to identify drugs that could be used for this very common peripheral neuropathy.
John Svaren, PhD
1500 Highland Avenue
Madison, WI 53705
PhD, Molecular Physiology, Vanderbilt University, Nashville, TN
Role of EGR and NAB proteins in peripheral nerve myelination; genomic analysis of physiological regulation; role of chromatin structure in gene regulation
Hung H, Kohnken R, Svaren J. The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. J Neurosci. 2012 Feb 1;32(5):1517-27.
Jang SW, Lopez-Anido C, Macarthur R, Svaren J, Inglese J. Identification of Drug Modulators Targeting Gene-Dosage Disease CMT1A. ACS Chem Biol. 2012 Jul 20;7(7):1205-13. Epub 2012 May 2.
Hodonsky CJ, Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA, Srinivasan R, Svaren J, McCallion AS, Antonellis A. SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Mol Cell Neurosci. 2012 Feb;49(2):85-96. Epub 2011 Oct 19.
Prasad MK, Reed X, Gorkin DU, Cronin JC, McAdow AR, Chain K, Hodonsky CJ, Jones EA, Svaren J, Antonellis A, Johnson SL, Loftus SK, Pavan WJ, McCallion AS. SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer. BMC Dev Biol. 2011 Jun 14;11:40.
Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, Nave KA, Kim HA, Olson EN, Lu QR. HDAC-mediated deacetylation of NF- κB is critical for Schwann cell myelination. Nat Neurosci. 2011 Apr;14(4):437-41. Epub 2011 Mar 20.
Jones, E.A., Lopez-Anido, C., Srinivasan, R., Krueger, C., Chang, L.W., Nagarajan, R., and Svaren, J. (2011) Regulation of the PMP22 gene through an intronic enhancer, Journal of Neuroscience, 31:4242-4250
Jang, S.W., Srinivasan, R., Jones, E.A., Sun, G., Keles, S., Krueger, C., Chang, L.W., Nagarajan, R., and Svaren, J. (2010) Locus-wide identification of EGR2/Krox20 regulatory targets in myelin genes, Journal of Neurochemistry 115:1409-1420.
Jang, S.W. and Svaren, J. (2009) Induction of myelin protein zero by early growth response 2 through upstream and intragenic elements. Journal of Biological Chemistry 284: 20111-20.
Mager, G.M., Ward, R.M., Srinivasan, R., Jang, S.W., Wrabetz, L., and Svaren, J. (2008) Active gene repression by the EGR2/NAB complex during peripheral nerve myelination, Journal of Biological Chemistry 283: 18187-18197
Jones, E.A., Jang, S.W., Mager,G.M., Chang, L-W., Srinivasan, R., Gokey, N.G., Ward, R.M., Nagarajan, R., Svaren, J. (2007) Interactions of Sox10 and Egr2 in myelin gene regulation. Neuron Glia Biology 3:377-387