Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome.
The copper-zinc superoxide dismutase (CuZnSOD) gene resides on chromosome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic CuZnSOD mice with elevated levels of CuZnSOD were used to determine whether, as in DS, overexpression of CuZnSOD was also associated with thymus and bone marrow abnormalities. Three independently derived transgenic CuZnSOD strains had abnormal thymi showing diminution of the cortex and loss of corticomedullary demarcation, resembling thymic defects in children with DS. Transgenic CuZnSOD mice were also more sensitive than control mice to in vivo injection of lipopolysaccharide (LPS), reflected by an earlier onset and enhanced apoptotic cell death in the thymus. This higher susceptibility to LPS-induced apoptosis was associated with an increased production of hydrogen peroxide and a higher degree of lipid peroxidation. When cultured under suboptimal concentrations of interleukin 3 or in the presence of tumour necrosis factor, bone marrow cells from transgenic CuZnSOD mice produced 2- to 3-fold less granulocyte and macrophage colonies than control. The results indicate that transgenic CuZnSOD mice have certain thymus and bone marrow abnormalities which are similar to those found in DS patients, and that the defects are presumably due to an increased oxidative damage resulting in enhanced cell death by apoptosis.
Peled-Kamar
M
M
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Lotem
J
J
Okon
E
E
Sachs
L
L
Groner
Y
Y
D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D004314:Down Syndrome / Q000209:etiology*; D005434:Flow Cytometry; D006098:Granulocytes; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation; D008264:Macrophages; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology*; D013950:Thymus Gland / Q000002:abnormalities*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase