1. PLoS One. 2010 Sep 15;5(9):e12716. doi: 10.1371/journal.pone.0012716.
Fine-mapping resolves Eae23 into two QTLs and implicates ZEB1 as a candidate gene
regulating experimental neuroinflammation in rat.
Stridh P(1), Thessen Hedreul M, Beyeen AD, Adzemovic MZ, Laaksonen H, Gillett A,
Ockinger J, Marta M, Lassmann H, Becanovic K, Jagodic M, Olsson T.
Author information:
(1)Center for Molecular Medicine, Department of Clinical Neuroscience,
Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
pernilla.strid@ki.se
BACKGROUND: To elucidate mechanisms involved in multiple sclerosis (MS), we
studied genetic regulation of experimental autoimmune encephalomyelitis (EAE) in
rats, assuming a conservation of pathogenic pathways. In this study, we focused
on Eae23, originally identified to regulate EAE in a (LEW.1AV1xPVG.1AV1)F2 cross.
Our aim was to determine whether one or more genes within the 67 Mb region
regulate EAE and to define candidate risk genes.
METHODOLOGY/PRINCIPAL FINDINGS: We used high resolution quantitative trait loci
(QTL) analysis in the 10th generation (G10) of an advanced intercross line (AIL)
to resolve Eae23 into two QTLs that independently regulate EAE, namely Eae23a and
Eae23b. We established a congenic strain to validate the effect of this region on
disease. PVG alleles in Eae23 resulted in significant protection from EAE and
attenuated CNS inflammation/demyelination. Disease amelioration was accompanied
with increased levels of Foxp3(+) cells in the CNS of the congenic strain
compared to DA. We then focused on candidate gene investigation in Eae23b, a 9 Mb
region linked to all clinical phenotypes. Affymetrix exon arrays were used to
study expression of the genes in Eae23b in the parental strains, where none
showed differential expression. However, we found lower expression of exon 4 of
ZEB1, which is specific for splice-variant Zfhep1. ZEB1 is an interleukin 2 (IL2)
repressor involved in T cell development. The splice-specific variance prompted
us to next analyze the expression of ZEB1 and its two splice variants, Zfhep1 and
Zfhep2, in both lymph node and spleen. We demonstrated that ZEB1 splice-variants
are differentially expressed; severity of EAE and higher IL2 levels were
associated with down-regulation of Zfhep1 and up-regulation of Zfhep2.
CONCLUSIONS/SIGNIFICANCE: We speculate that the balance between splice-variants
of ZEB1 could influence the regulation of EAE. Further functional studies of ZEB1
and the splice-variants may unravel novel pathways contributing to MS
pathogenesis and inflammation in general.
PMCID: PMC2939884
PMID: 20856809 [PubMed - indexed for MEDLINE]
PUBMED: 20856809
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