The impact of genetic background and Bid on the phenotype of Bcl-2-deficiency in mice.
How a central apoptosis mechanism could be modulated during a specific developmental or homeostatic process to comply with the specific needs of a particular tissue is poorly understood. Bcl-2 is a key anti-apoptosis regulator and its deletion resulted in multiple defects in mice, indicating its broad involvement in development and homeostasis of various tissues. We found that the severity and extensiveness of the defects could be greatly influenced by the genetic background of the mice. Hence, Bcl-2-deficient mice predominantly on C57BL/6 background had the most severe presentation with increased embryonic lethality, whereas Bcl-2-deficient mice predominantly on 129/SvJ background had a significantly minor phenotype. In particular, the 129/SvJ background could almost completely rescue the polycystic kidney disease phenotype of the Bcl-2 deficiency, resulting in normal renal functions. These observations would be consistent with the assumption that the C57BL/6 background is more pro-death while the 129/SvJ background is more pro-survival. Concurrent deletion of Bid, a BH3-only molecule, in either genetic background, could significantly increase the birth rate of the Bcl-2 deficient progenies and lessen lymphocytopenia, although the double knockout mice still developed the polycystic kidney diseases. Overall, our work indicates that the phenotype of Bcl-2 deficiency can be affected by multiple genetic elements, resulting in tissue-specific modulations of the cell death program during development and cellular homeostasis.
Ni
Hong-Min
HM
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. xmyin@pitt.edu
Chen
Xiaoyun
X
Chen
Lei
L
DiFrancesca
Daniell
D
Harada
Hisashi
H
Yin
Xiao-Ming
XM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D008231:Lymphopenia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2