Abstract
BackgroundAcute hypoxic/ischemic insults to the forebrain, often resulting in significant cellular loss of the cortical parenchyma, are a major cause of debilitating injury in the industrialized world. A clearer understanding of the pro-death/pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage.Methodology/Principal FindingsWe demonstrate here that the transcriptional repressor ZEB1, thought to be involved in regulating the timing and spatial boundaries of basic-Helix-Loop-Helix transactivator-mediated neurogenic determination/differentiation programs, functions to link a pro-survival transcriptional cascade rapidly induced in cortical neurons in response to experimentally induced ischemia. Employing histological, tissue culture, and molecular biological read-outs, we show that this novel pro-survival response, initiated through the rapid induction of p63, is mediated ultimately by the transcriptional repression of a pro-apoptotic isoform of p73 by ZEB1. We show further that this phylogenetically conserved pathway is induced as well in the human cortex subjected to episodes of clinically relevant stroke.Conclusions/SignificanceThe data presented here provide the first evidence that ZEB1 induction is part of a protective response by neurons to ischemia. The stroke-induced increase in ZEB1 mRNA and protein levels in cortical neurons is both developmentally and phylogenetically conserved and may therefore be part of a fundamental cellular response to this insult. Beyond the context of stroke, the finding that ZEB1 is regulated by a member of the p53 family has implications for cell survival in other tissue and cellular environments subjected to ischemia, such as the myocardium and, in particular, tumor masses.
Highlights
Hypoxic/Ischemic (H-I) insult to the CNS is an important cause of neurological morbidity, with severe cases resulting in life-long deficits [1,2]
Beyond the context of stroke, the finding that ZEB1 is regulated by a member of the p53 family has implications for cell survival in other tissue and cellular environments subjected to ischemia, such as the myocardium and, in particular, tumor masses
A recent report demonstrating that a shift in intracellular redox levels to a net reducing environment dramatically increased the functional activity of a ZEB1 co-repressor, C-terminal binding protein 1 [CtBP1; 22], prompted us to ask whether ZEB1 may itself be subject to regulation by O2 levels in the brain
Summary
Hypoxic/Ischemic (H-I) insult to the CNS is an important cause of neurological morbidity, with severe cases resulting in life-long deficits [1,2]. Histological studies in embryonic mice reveal a tremendous amount of cellular death in the developing cortex, in both neural progenitor and newly born neuronal populations, peaking at roughly 70% of the total cell number around embryonic day 14, and declining thereafter [11]. Work from a number of labs has implicated the involvement of transcriptionally active isoforms of p53 and p63 in this process [12,13] and TAp63 has been shown to be required for growth factor-deprivation-mediated apoptosis of developing sympathetic neurons [14]. A clearer understanding of the pro-death/ pro-survival signaling pathways and their downstream targets is critical to the development of therapeutic interventions to mitigate permanent neurological damage
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