Allelic variation in the Tyk2 and EGF genes as potential genetic determinants of CNS repair.
The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler's virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2(q)/SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T(H)1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.
Bieber
Allan J
AJ
Molecular Neuroscience Program and Departments of Neurology and Immunology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. bieber.allan@mayo.edu
Suwansrinon
Kanitta
K
Kerkvliet
Jason
J
Zhang
Weidong
W
Pease
Larry R
LR
Rodriguez
Moses
M
D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D004249:DNA Damage; D004260:DNA Repair; D003711:Demyelinating Diseases / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000235:genetics*; D014644:Genetic Variation; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000235:genetics; D053634:TYK2 Kinase / Q000235:genetics*
D017467:Receptors, Erythropoietin; D004815:Epidermal Growth Factor; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse