title: Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains.
abstract: 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.
authors.affiliation: Umeå Center for Molecular Medicine, University of Umeå, Umeå, Sweden.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Bergman
authors.forename: Nadia
authors.initials: N
authors.lastname: Duarte
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Marie
authors.initials: M
authors.lastname: Lundholm
authors.forename: Vinicius
authors.initials: V
authors.lastname: Motta
authors.forename: Kristina
authors.initials: K
authors.lastname: Lejon
authors.forename: Carlos
authors.initials: C
authors.lastname: Penha-Gonçalves
authors.forename: Dan
authors.initials: D
authors.lastname: Holmberg
mesh_terms: 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
chemical_list: D005819:Genetic Markers; D003907:Dexamethasone