Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains.
Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.
Bergman
Marie-Louise
ML
Umeå Center for Molecular Medicine, University of Umeå, Umeå, Sweden.
Duarte
Nadia
N
Campino
Susana
S
Lundholm
Marie
M
Motta
Vinicius
V
Lejon
Kristina
K
Penha-Gonçalves
Carlos
C
Holmberg
Dan
D
D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013045:Species Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D005819:Genetic Markers; D003907:Dexamethasone