Loss of BH3-only protein Bim inhibits apoptosis of hemopoietic cells in the fetal liver and male germ cells but not neuronal cells in bcl-x-deficient mice.
Members of the Bcl-2 family include pro- and antiapoptotic proteins that regulate programmed cell death of developing tissues and death in response to cellular damage. In developing mice, the antiapoptotic Bcl-x(L) is necessary for survival of neural and hematopoietic cells, and consequently, bcl-x-deficient mice die around Day 13.5 of embryogenesis. Furthermore, adult bcl-x(+/-) heterozygous male mice have reduced fertility because of testicular degeneration. Bax, a multi-BH (Bcl-2 homology) domain proapoptotic member of the Bcl-2 family, is regulated by Bcl-x(L) and is required for the neuropathological abnormalities seen in bcl-x-deficient embryos. The BH3 domain only subgroup of the Bcl-2 family includes proapoptotic members that are essential for the initiation of apoptotic signaling. In this study, we investigated the role for Bim, a BH3 domain only protein, in the embryonic lethality and increased developmental cell death in bcl-x-deficient animals and the perturbed testicular function in bcl-x(+/-) adults. Our studies show that bim deficiency attenuates hematopoietic cell death in the fetal liver of bcl-x-deficient animals, indicating that Bim contributes to programmed cell death in this cell population. In addition, we found that testicular degeneration of adult bcl-x(+/-) males was rescued by concomitant Bim deficiency. However, concomitant Bim deficiency had no effect on the embryonic lethality and widespread nervous system abnormalities caused by bcl-x deficiency. Our work identifies Bim as an important regulator of bcl-x deficiency-induced cell death during hematopoiesis and testicular development.
Akhtar
Rizwan S
RS
Division of Neuropathology, Department of Pathology, University of Alabama-Birmingham SC 961, 1530 3rd Avenue South, Birmingham, AL 35294-0017, USA.
Klocke
Barbara J
BJ
Strasser
Andreas
A
Roth
Kevin A
KA
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D013737:Testis / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D051020:bcl-X Protein / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein