isoform Mcl-1S lacks BH1 and BH2 domains due to the exclusion of exon 2 during splicing. While Mcl-1L could enhance cell survival, the alternatively spliced Mcl-1S was shown to be associated with apoptosis induction26,42. In addition to its role in the regulation of apoptosis, Mcl-1 plays a key role in nervous system development and neuronal cell death. Neuronal precursors within the ventricular zone and newly committed neurons in the cortex are shown to express high levels of Mcl-143 and Mcl-1 upregulation has been shown to have a role in survival of neuronal precursor cells44. Here we also show that EtOH-mediated reduction in Mcl-1L and increase in Mcl-1S isoforms lead to the activation of apoptosis and cell death in neural progenitors. In addition, overexpression of Mcl-1L isoform can prevent ethanol-induced cell death. On the other hand, overexpression of Mcl-1S isoform in neural progenitors was not sufficient to induce apoptosis or cell toxicity, suggesting that Mcl-1S may be the ineffective form of Mcl-1L. These results suggest that Mcl-1L is likely the key player in the mechanism of increased susceptibility of neural progenitors to the toxic effects of EtOH.
