[1621] Neural Stem Cells Deficient in BAX and BAK Manifest Profound Hyperplasia and Tumorigenesis.

Samuel G Katz, Jill K Fisher, Keith L Ligon, Loren D Walensky. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA; Dana Farber Cancer Institue, Harvard Medical School, Boston, MA

Background: BCL-2 family members are key regulators of the intrinsic pathway of programmed cell death or apoptosis. BAX and BAK are believed to have overlapping roles as the ultimate gatekeepers of mitochondrial apoptosis. Once activated, both proteins form homo-oligomers that induce permeabilization of the outer mitochondrial membrane, enabling released mitochondrial factors to activate caspases, which irreversibly execute the death program. Deletion of pro-apoptotic BAX and BAK from fibroblasts results in marked resistance to a variety of death stimuli. Double knock-out mice are predominantly non-viable and the survivors exhibit multiple developmental abnormalities, including excess neural stem cells in the periventricular region, hippocampus, cerebellum and olfactory bulb regions of the brain.
Design: To further explore the pathophysiology of Bax/Bak deletion in the adult central nervous system, we generated mice globally deficient in Bak with a conditional deletion of Bax in Nestin-positive cells.
Results: As anticipated, these mice develop proliferations of neural progenitor/stem cells within the subventricular zone (SVZ) niche, yet the degree of accumulation in adult brain is profound and includes a distinctive pattern of growth in rosettes. Furthermore, rare mice develop large brain masses, which in two cases were composed of benign-appearing, mature neurons, but in one animal appeared aggressive.
Conclusions: These studies underscore the importance of BAX and BAK in regulating Nestin-positive progenitor cell pools, with loss of function predisposing to both benign and malignant tumorigenesis.
Category: Neuropathology

Tuesday, March 1, 2011 1:00 PM

Poster Session IV # 244, Tuesday Afternoon


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