Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Oct 29;23(30):9817-23.
doi: 10.1523/JNEUROSCI.23-30-09817.2003.

Discrete Gene Loci Regulate Neurodegeneration, Lymphocyte Infiltration, and Major Histocompatibility Complex Class II Expression in the CNS

Affiliations
Free PMC article

Discrete Gene Loci Regulate Neurodegeneration, Lymphocyte Infiltration, and Major Histocompatibility Complex Class II Expression in the CNS

Olle Lidman et al. J Neurosci. .
Free PMC article

Abstract

Neurodegeneration and inflammation are fundamental aspects of many neurological diseases. A genome-wide scan of the response to ventral root avulsion (VRA) in a rat F2 cross discloses specific gene regions that regulate these processes. Two gene loci displayed linkage to neurodegeneration and T cell infiltration, respectively, and a single locus displayed extreme linkage to VRA-induced major histocompatibility complex class II expression on microglia. The demonstration that polymorphic genes in different loci control neurodegeneration and CNS inflammation has implications for various experimental rodent nervous system paradigms and potentially for genetically regulated susceptibility to a variety of human CNS diseases.

Figures

Figure 1.
Figure 1.
Genotyping and analysis of phenotype in the F2 cross. a, Schematic illustration of the genotype in parental (P), F1, and F2 generations, where an average of one or two recombinations per chromosome can be expected in F2 animals. b, Genotyping was performed with a total of 177 microsatellite markers on genomic DNA from each animal to construct a genetic map. c, Low magnification micrograph of a rat spinal cord 2 weeks after VRA with arrows indicating the avulsed roots. Scale bar, 2mm. d, Cresyl violet counterstained section demonstrating loss of motoneurons on the side of the lesion (arrow). Scale bar, 1 mm. e–g, Immunolabeling demonstrates increased staining for CD11b/c (e), MHC class II (f), and GFAP (g) in the ventral horn on the lesioned side.
Figure 2.
Figure 2.
Genetic regulation of nerve injury-induced neurodegeneration. a, Relative motoneuron numbers (ratio between lesioned and contralateral sides; base 10 logarithm) in DA, PVG, F1, and F2 populations, with the median indicated. b, Micrographs of cresyl violet counterstained spinal cord sections demonstrating increased loss of motoneurons in the DA strain compared with PVG. Scale bar, 0.5 mm. Higher magnification micrographs of the lesioned side of the cord are shown to the right. Scale bar, 0.2 mm. c, Genome-wide LOD score plot for linkage to neurodegeneration in the F2 population. Threshold for significant linkage at 95% CI (dashed line) and the location of VRA1 and VRA2 are given. d, LOD score plot of the VRA1 QTL on rat chromosome 8. Dashed line indicates threshold for significant linkage at 95% CI. e, Survival of motoneurons (base 10 logarithm) in the F2 population stratified for genotype at the max marker of VRA1 (D8Rat205), demonstrating reduced survival in rats homozygous for the DA allele. Lines indicate the median. f, Micrographs of cresyl violet counterstained sections from representative animals homozygous for the DA allele (DA/DA), homozygous for the PVG allele (PVG/PVG), and heterozygous (DA/PVG) in VRA1 (D8Rat205). Scale bar, 0.5 mm. Higher magnification micrographs of the lesioned side are shown to the right. Scale bar, 0.2 mm. g, LOD score plot for VRA2 QTL at the centromeric end of chromosome 5 in the F2 population. Dashed line indicates threshold for significant linkage at 95% CI.
Figure 3.
Figure 3.
Genetic regulation of T cell infiltration. a, Micrograph showing infiltrating CD3+ cells in the ventral horn of a DA rat. Scale bar, 0.2 mm. b, The number of CD3+ cells in the ventral horn after VRA demonstrates a strain-dependent influence, with higher cell counts in DA rats. Lines indicate the median. No clear gene dosage effect is evident in the F1 population. c, LOD score plot of the VRA2 and VRA3 QTLs on chromosome 5. d, Genome-wide LOD score plot for linkage to T cell infiltration in the F2 population. Threshold for significant linkage at 95% CI (dashed line) and the location of VRA2 and VRA3 are indicated. e, CD3+cell numbers in the F2 population stratified for genotype at the max marker of VRA2 (D5Rat70), demonstrating increased cell numbers in animals homozygous for the DA allele.
Figure 4.
Figure 4.
Genetic regulation of MHC class II expression. a–c, Micrographs showing MHC class II immunolabeling in the ventral horn of a DA (a), PVG (b), and F1 (c) rat. Scale bar, 1 mm. d, MHC class II-labeled surface area (base 10 logarithm) in DA, PVG, F1, and F2 populations, with the median indicated. The 0.99 (log10) difference between DA and PVG corresponds to an almost 10-fold difference in real terms. The intermediate outcome in the F1 population suggests a gene dosage effect. e, Genome-wide LOD score plot for linkage to MHC class II-labeling in the F2 population. Threshold for significant linkage at 95% CI (dashed line) and the location of VRA4 and the MHC complex are indicated. f, LOD score plot of the VRA4 QTL on chromosome 10. g–i, Micrographs showing immunolabeling for MHC class II in the ventral horn of F2 rats stratified for the max marker of VRA4 (D10Rat95), demonstrating a much more vigorous response in rats homozygous for the DA allele (g) compared with PVG homozygous (h) and heterozygous (i) animals. Scale bar, 1 mm. j, MHC class II-labeled surface area in F2 rats stratified for haplotype at the max marker of VRA4 (D10Rat95).

Similar articles

See all similar articles

Cited by 10 articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

Feedback