title: Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Hutcheson
authors.forename: John C
authors.initials: JC
authors.lastname: Scatizzi
authors.forename: Emily
authors.initials: E
authors.lastname: Bickel
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001772:Blood Cell Count; D002352:Carrier Proteins / Q000235:genetics; D003433:Crosses, Genetic; D006410:Hematopoiesis / Q000235:genetics*; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007962:Leukocytes / Q000378:metabolism; D008214:Lymphocytes / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000235:genetics; D013950:Thymus Gland / Q000002:abnormalities*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein