Apoptosis in cerebrum of macular mutant mouse.
Neuronal cell death in the brain of macular mutant mouse, a model of copper metabolism abnormality, has features of both apoptosis and necrosis. Apoptotic cells were morphologically identified by the terminal deoxynucleotidyl transferase nick end-labeling (TUNEL) method and electron microscopy. Numerous TUNEL-positive cells were identified in the cerebral cortex, hippocampus and thalamus of the hemizygotes after postnatal day 11. Ultramicroscopic studies confirmed that a number of cells had apoptotic features characterized by condensation and segregation of the nuclei. Furthermore, genomic DNA gel electrophoresis revealed a laddering pattern in the hemizygous brain. Starvation, which produced a low body weight in normal mice similar to that seen in the hemizygotes, did not result in an increase of TUNEL-positive cells. We also found that there was no increase of apoptotic cells in the brains of heterozygotes and copper-supplemented hemizygotes. Immunocytochemical analysis revealed that the distribution of copper/zinc superoxide dismutase-containing cells differed from that of TUNEL-positive cells. These findings suggest that copper deficiency is a key factor triggering apoptosis in the brain of macular mutant mouse through a mechanism different from suppression of antioxidant action of the dismutase. The improved survival period of the copper-supplemented hemizygotes may be attributed, in part, to inhibition of excessive neuronal apoptosis identified in the late stage of the disease.
Ohno
Masaki
M
Department of Pediatrics, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu 520-2192, Japan. ohno@belle.shiga-med.ac.jp
Narita
Tsutomu
T
Abe
Junko
J
Tsuzuki
Tomoko
T
Yagi
Kumiyo
K
Takikita
Shoichi
S
Takano
Tomoyuki
T
Shimada
Morimi
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000503:physiopathology* / Q000648:ultrastructure; D003300:Copper / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D004587:Electrophoresis, Agar Gel; D006579:Heterozygote; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains / Q000502:physiology*; D012016:Reference Values; D013482:Superoxide Dismutase / Q000378:metabolism
D003300:Copper; D004247:DNA; D013482:Superoxide Dismutase