John Svaren
Ph.D., Vanderbilt University
Faculty Director, Cellular and Molecular Neurosciences Core
Associate Professor, Comparative Biosciences

Contact Information:
Waisman Center
UW-Madison
1500 Highland Avenue
Madison, WI 53705
Phone: (608) 263-4246
Fax: (608) 263-3926
E-mail: jpsvaren@wisc.edu
Svaren Lab Home Page
School of Veterinary Medicine
Inherited Peripheral Neuropathies Mutation Database

Research Statement

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. Some peripheral neuropathiesincluding Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas Syndrome (DSS), and Congenital Hypomyelinating Neuropathy (CHN)are caused by deficits in myelin formation and maintenance by Schwann cells. Most of the genetic causes of these peripheral neuropathies have been traced to mutations in genes coding for myelin-associated proteins (e.g. myelin protein zero). However, mutations in the gene coding for the EGR2 transactivator have recently been associated with these diseases, confirming previous work showing that the EGR2/Krox-20 is a critical regulator of myelin formation in mouse development. The identification of a critical transcriptional activator in the myelination process has allowed us an opportunity to understand how coordinated regulation of many genes contributes to the myelination process.

Our research goal 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. The evidence suggests that the dominant mutants effectively sequester a critical cofactor of EGR2 activity, and studies of protein-protein interactions have suggested that interaction with another regulator, Sox10, is critically involved. 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. Therefore, we are also focusing on the use of both gene microarrays and quantitative PCR assays to try to understand how EGR2 and NAB proteins regulate a gene network that controls myelination of peripheral nerves by Schwann cells.

The spectrum of peripheral myelinopathies (including CMT, DSS, and CHN) cause a variety of clinical problems and the more severe cases often result in premature death due to decreased respiratory function. However, there is great promise for therapies that treat this type of disease since the affected Schwann cells remain viable during the course of the disease. Even in more severe cases, the normal time of myelin formation (during the first year of life) should allow restorative therapy in those cases where a specific genetic cause is identified. Other types of therapy based on rapidly developing stem cell technologies are also strong possibilities. Because EGR2 coordinates gene regulation events that are vital for proper myelination of peripheral nerves, development of any of these therapies will clearly benefit from elucidation of the genetic program controlled by EGR2 and NAB proteins.

Representative Publications

Svaren J, Meijer D.(2008) The molecular machinery of myelin gene transcription in Schwann cells. Glia. 2008 Nov 1;56(14):1541-51. Review.

Mager GM, Ward RM, Srinivasan R, Jang SW, Wrabetz L, Svaren J. (2008) Active gene repression by the Egr2.NAB complex during peripheral nerve myelination. Journal of Biological Chemistry. Jun 27;283(26):18187-97.

Tureyen K, Brooks N, Bowen K, Svaren J, Vemuganti R. (2008) Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia. Journal of Neurochemistry. May;105(4):1313-24.

Jones EA, Jang SW, Mager GM, Chang LW, Srinivasan R, Gokey NG, Ward RM, Nagarajan R, Svaren J. (2007) Interactions of Sox10 and Egr2 in myelin gene regulation. Neuron Glia Biology. Nov;3(4):377-87.

LeBlanc, S.E., Jang, S.W., Ward, R.M., Wrabetz, L., and Svaren, J. Direct regulation of myelin protein zero expression by the Egr2 transactivator. (2006) Journal of Biological Chemistry, 281(9):5453-60.

LeBlanc, S.E., Srinivasan, R., Ferri, C., Mager, G.M., Gillian-Daniel, A.L., Wrabetz, L., and Svaren, J. (2005) Regulation of lipid/cholesterol biosynthetic genes by Egr2/Krox-20 and the SREBP pathway during peripheral nerve myelination, Journal of Neurochemistry, 93:737-748.

Gillian-Daniel, A.L. and Svaren, J. (2004) The Ddx20/DP103 Dead Box Protein Represses Transcriptional Activation by Egr2/Krox-20, Journal of Biological Chemistry, 279:9056-63

Svaren, J., Sevetson, B.R., Golda, T., Stanton, J., Swirnoff, A.H., and Milbrandt, J. (1998) Novel Mutants of NAB Corepressors Enhance Activation by Egr Transactivators. EMBO Journal 17, 6010-6019

Warner, L.E., Svaren, J., Milbrandt, J., and Lupski, J.R. (1999) Functional consequences of mutations in the early growth response 2 (EGR2) gene associated with human myelinopathies. Human and Molecular Genetics 8, 1245-1251.

Nagarajan, R., Svaren, J., Le, N., Araki T., Watson, M., and Milbrandt, J. (2001) EGR2 mutations in inherited neuropathies dominant negatively inhibit myelin gene expression. Neuron 30:355-368.

Venken, K., Di Maria, E., Bellone, E., Balestra, P., Cassandrini, D., Mandich, P., De Jonghe, P., Timmerman, V., Svaren, J. (2002) Search for mutations in the EGR2 corepressor proteins, NAB1 and NAB2, in human peripheral neuropathies. Neurogenetics, 4:37-41.