Alteration of apoptotic protease-activating factor-1 (APAF-1)-dependent apoptotic pathway during development of rat brain and liver.
Brain and liver extracts of rats at different stages after birth were examined for cytochrome c/dATP-dependent caspase (DEVDase)-activation (mitochondria pathway) in vitro. The caspase-activating activity in the brain extracts rapidly decreased after birth, reaching approximately 50 and 5%, at 1 and 2 weeks, respectively, of that in a 3-days- newborn sample, and essentially no caspase-activation was detected in the adult rat brain extracts. Such a dramatic change was not detected in the liver samples, suggesting that the observed abrogation of the cytochrome c-dependent mitochondria pathway after birth is a brain-specific event. In order to determine the factor(s) lacking in adult brain, we separately measured Apaf-1, procaspase 9, and pro-DEVDase activities using a supplementation assay. In adult brain, Apaf-1 activity was scarcely detected, while the tissue retained low but significant amounts of procaspase 9 (16% of that in the fetal tissue) and a pro-DEVDase (3.4%). In contrast, adult liver extracts retained relatively high levels of all of these factors. Immunoblot analyses clearly indicated that the expression of Apaf-1 and procaspase 3 is markedly suppressed within 4 weeks after birth in brain tissue while they are even expressed in adult liver. Considering these results together, we propose that, in the brain, the cytochrome c-dependent mitochondria pathway, which is essential for the programmed cell death during normal morphogenesis, is abrogated within 2-4 weeks after birth, whereas the pathway is still active in other adult tissues such as liver.
Ota
Katsuya
K
Department of Biochemistry, Nara Medical University, Kashihara, Nara 634-8521, Japan.
Yakovlev
Alexander G
AG
Itaya
Asako
A
Kameoka
Masanori
M
Tanaka
Yasuharu
Y
Yoshihara
Koichiro
K
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D009928:Organ Specificity; D010447:Peptide Hydrolases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D010447:Peptide Hydrolases; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; C108711:DEVDase