Although zinc has been implicated in the functionality of the hippocampus since the 1970's, the recent discovery of adult neuronal stem cells in this region of the brain provides the potential for novel zinc-regulated hippocampal processes. The current work addressed the role of zinc in the proliferation, maintenance, and survival of neuronal precursor cells. First, this work employed a genome-wide analysis of the effect of dietary zinc deficiency in the hippocampus. The data revealed that 3 weeks of dietary zinc deficiency resulted in the down-regulation of nearly 400 genes, many of which were associated with synaptic plasticity (stau2, syn1), neurotransmitter receptors (grin1, gabrb3), neurogenesis (iguana, id2, nek9), and cell viability (sod2, stat3). Furthermore, using a candidate gene approach, the current work shows a vital role of zinc in p53-mediated mechanisms governing proliferation and apoptosis of neuronal precursor cells. For example, zinc deficient cells show increased nuclear and mitochondrial translocation of the tumor suppressor p53. Using a dominant negative construct to ensure p53 regulation, this work shows that nuclear p53 is responsible for the downstream target genes responsible for cell cycle arrest (reprimo, lats2). These data coincide with a decrease in BrdU-labeling. The current work also highlights initial protective responses governed by the transcription factor p53. However, zinc deficient neuronal precursors also show a p53-dependent increase in mitochondrial reactive oxygen species which could be mediated by a decreased expression of glutathione peroxidase mRNA and mitochondrial localized p53. If the deficiency is severe or prolonged nuclear p53 regulates expression of apoptotic genes (rb1, tgf-β) whereas, mitochondrial p53 mediates interactions with Bcl-family proteins to initiate a loss in mitochondrial membrane potential. Ultimately, the current work adds to the essential role of zinc in the hippocampus and identifies a novel mechanism for zinc in the regulation of neuronal precursor proliferation, maintenance, and survival.
