Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice.
Apoptosis of the developing metanephric kidney plays an important role in renal organogenesis. The bcl-2 is an oncogene that inhibits apoptotic cell death in a variety of settings. The bcl-2 (-/-) mice complete embryonic development but, in contrast to bcl-2 (+/-) and bcl-2 (+/+) littermates, manifest growth retardation, hypopigmentation of hair, lymphoid apoptosis, abnormal kidney morphology, and renal failure postnatally. To provide insight into the mechanism for the latter abnormalities, we examined metanephric kidneys from bcl-2 (-/-), bcl-2 (+/-), and bcl-2 (+/+) mice, as well as embryonic day 12 (E12) mouse embryos, and compared growth and development of metanephroi in vitro. Kidneys from bcl-2 (+/-) mice developed normally. In contrast, development of kidneys from bcl-2 (-/-) mice was abnormal as reflected by a marked reduction of renal size in newborns compared with kidneys of bcl-2 (+/-) littermates. In addition, kidneys from bcl-2 (-/-) mice contained far fewer nephrons and had smaller nephrogenic zones. Although metanephroi obtained from E12 bcl-2 (+/-) and bcl-2 (-/-) mouse embryos were comparable in size, apoptosis of cells within metanephric blastemas of metanephroi from E12 bcl-2 (-/-) embryos was strikingly enhanced compared with that in blastemas of metanephroi from bcl-2 (+/-) embryos. During 3 days in culture, growth and development of metanephroi from bcl-2 (-/-) embryos were visibly reduced compared with those from bcl-2 (+/-) embryos.(ABSTRACT TRUNCATED AT 250 WORDS)
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110.
C M
CM
Sorenson
S A
SA
Rogers
S J
SJ
Korsmeyer
M R
MR
Hammerman
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003433:Crosses, Genetic; D005314:Embryonic and Fetal Development; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology* / Q000473:pathology; D007672:Kidney Cortex / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009399:Nephrons / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology; D009857:Oncogenes; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003404:Creatinine