title: Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK.
abstract: The proapoptotic BCL-2 family proteins BAX and BAK serve as essential gatekeepers of the intrinsic apoptotic pathway and, when activated, transform into pore-forming homo-oligomers that permeabilize the mitochondrial outer membrane. Deletion of Bax and Bak causes marked resistance to death stimuli in a variety of cell types. Bax(-/-)Bak(-/-) mice are predominantly non-viable and survivors exhibit multiple developmental abnormalities characterized by cellular excess, including accumulation of neural progenitor cells in the periventricular, hippocampal, cerebellar and olfactory bulb regions of the brain. To explore the long-term pathophysiological consequences of BAX/BAK deficiency in a stem cell niche, we generated Bak(-/-) mice with conditional deletion of Bax in Nestin-positive cells. Aged Nestin(Cre)Bax(fl/fl)Bak(-/-) mice manifest progressive brain enlargement with a profound accumulation of NeuN- and Sox2-positive neural progenitor cells within the subventricular zone (SVZ). One-third of the mice develop frank masses comprised of neural progenitors, and in 20% of these cases, more aggressive, hypercellular tumors emerged. Unexpectedly, 60% of Nestin(Cre)Bax(fl/fl)Bak(-/-) mice harbored high-grade tumors within the testis, a peripheral site of Nestin expression. This in vivo model of severe apoptotic blockade highlights the constitutive role of BAX/BAK in long-term regulation of Nestin-positive progenitor cell pools, with loss of function predisposing to adult-onset tumorigenesis.
authors.affiliation: Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Katz
authors.forename: J K
authors.initials: JK
authors.lastname: Fisher
authors.forename: M
authors.initials: M
authors.lastname: Correll
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: K L
authors.initials: KL
authors.lastname: Ligon
authors.forename: L D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000209:etiology*; D006965:Hyperplasia; D007381:Intermediate Filament Proteins / Q000032:analysis; D008297:Male; D058627:Megalencephaly / Q000209:etiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis; D064231:Nestin; D058953:Neural Stem Cells / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D013736:Testicular Neoplasms / Q000209:etiology*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000032:analysis / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000502:physiology*
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein