bcl-2/Adenovirus E1B 19 kDa Interacting Protein-3 (BNIP3) Regulates Hypoxia-Induced Neural Precursor Cell Death

• Published in: Journal of neuropathology and experimental neurology 2009-12, Vol.68 (12), p.1326-1338
• Main Authors: Walls, K.C., Ghosh, Arindam P., Ballestas, Mary E., Klocke, Barbara J., Roth, Kevin A.
• Format: Article
• Language: English
• ISSN: 0022-3069
• DOI: 10.1097/NEN.0b013e3181c3b9be

Perinatal hypoxia-ischemia (HI) may result in long-term neurological deficits. In addition to producing neuron death, HI causes death of neural precursor cells (NPCs) in the developing brain. To characterize the molecular pathways that regulate hypoxia-induced death of NPCs, we treated a mouse neural stem cell line (C17.2 cells) and fibroblastic growth factor-II-expanded primary NPCs derived from wild-type or gene-disrupted mice, with oxygen glucose deprivation (OGD) or the hypoxia-mimetics desferrioxamine (DFO) or Cobalt chloride. NPCs undergoing hypoxia exhibited time- and concentration-dependent caspase-3 activation and cell death, which was significantly reduced by treatment with a broad caspase inhibitor or protein synthesis inhibition. Bax/Bak-deficient NPCs were protected from DFO-induced death and exhibited minimal caspase-3 activation. OGD or hypoxia-mimetic exposure also resulted in increased hypoxia inducible factor alpha and bcl-2/adenovirus E1B 19 kDa interacting protein-3 (BNIP3) expression. BNIP3 shRNA treatment failed to affect hypoxia-induced caspase-3 activation but inhibited cell death and nuclear translocation of apoptosis inducing factor, indicating that BNIP3 is an important regulator of caspase-independent NPC death following hypoxia. These studies demonstrate that hypoxia activates both caspase-dependent and -independent NPC death pathways that are critically regulated by multiple Bcl-2 family members.