The Journal of Experimental Medicine
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Published 20 June 2005. doi:10.1084/jem.20041484
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 12, 1949-1960
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ARTICLE

 Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis

Jack Hutcheson1, John C. Scatizzi1, Emily Bickel1, Nathaniel J. Brown1, Philippe Bouillet2, Andreas Strasser2, and Harris Perlman1

1 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
2 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia

CORRESPONDENCE Harris Perlman: perlmanh{at}slu.edu

The proapoptotic members of the Bcl-2 family can be subdivided into members that contain several Bcl-2 homology (BH) domains and those that contain only the BH3 domain. Although it is known that BH3-only proteins and the multi-BH domain proteins, Bak and Bax, are essential for programmed cell death, the overlapping role of these two subgroups has not been examined in vivo. To investigate this, we generated Bak/Bim and Bax/Bim double deficient mice. We found that although Bax–/–Bim–/–, but not Bak–/–Bim–/–, mice display webbed hind and front paws and malocclusion of the incisors, both groups of mice present with dysregulated hematopoiesis. Combined loss of Bak and Bim or Bax and Bim causes defects in myeloid and B-lymphoid development that are more severe than those found in the single knock-out mice. Bak–/–Bim–/– mice have a complement of thymocytes that resembles those in control mice, whereas Bax–/–Bim–/– mice are more similar to Bim–/– mice. However, thymocytes isolated from Bak–/–Bim–/– or Bax–/–Bim–/– mice are markedly more resistant to apoptotic stimuli mediated by the intrinsic pathway as compared with thymocytes from single-knockout mice. These data suggest an essential overlapping role for Bak or Bax and Bim in the intrinsic apoptotic pathway.

Abbreviations: 7-AAD, 7-amino–actinomycin D; BH, Bcl-2 homology; DKO, double KO; ES, embryonic stem.


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