Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK
S G Katz1, J K Fisher, M Correll
1Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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.
Insights
Loss of BAX and BAK proteins, crucial for programmed cell death, leads to uncontrolled neural progenitor cell growth. This deficiency causes brain enlargement and predisposes to adult-onset tumors in mice.
Area of Science:
- Cell Biology
- Developmental Biology
- Cancer Biology
Background:
- The BCL-2 family proteins BAX and BAK are critical regulators of the intrinsic apoptotic pathway.
- Activation of BAX and BAK leads to mitochondrial outer membrane permeabilization and programmed cell death.
- Complete BAX/BAK deficiency results in developmental abnormalities due to cellular excess.
Purpose of the Study:
- To investigate the long-term effects of BAX/BAK deficiency in stem cell niches.
- To model the consequences of impaired apoptosis in Nestin-positive progenitor cells.
Main Methods:
- Generation of conditional knockout mice (Nestin(Cre)Bax(fl/fl)Bak(-/-)).
- Analysis of aged mice for developmental abnormalities and tumor formation.
- Characterization of neural progenitor cell populations using NeuN and Sox2 markers.
Main Results:
- Aged Nestin(Cre)Bax(fl/fl)Bak(-/-) mice exhibited progressive brain enlargement and accumulation of neural progenitor cells in the SVZ.
- A significant proportion of these mice developed neural progenitor masses, with some progressing to aggressive tumors.
- Unexpectedly, high-grade tumors also emerged in the testes of 60% of the mice, a site of Nestin expression.
Conclusions:
- BAX/BAK are essential for the long-term regulation of Nestin-positive progenitor cell pools.
- Loss of BAX/BAK function predisposes to adult-onset tumorigenesis in both neural and peripheral stem cell niches.
- This model highlights the critical role of apoptosis in preventing progenitor cell overgrowth and cancer.
