TY - JOUR
T1 - Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis
AU - Hutcheson, Jack
AU - Scatizzi, John C.
AU - Bickel, Emily
AU - Brown, Nathaniel J.
AU - Bouillet, Philippe
AU - Strasser, Andreas
AU - Perlman, Harris
PY - 2005/6/20
Y1 - 2005/6/20
N2 - 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. JEM
AB - 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. JEM
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U2 - 10.1084/jem.20041484
DO - 10.1084/jem.20041484
M3 - Article
C2 - 15967824
AN - SCOPUS:22344434871
SN - 0022-1007
VL - 201
SP - 1949
EP - 1960
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -