Abstract
Expression of apoptotic protease activating factor-1 (Apaf-1) gradually decreases during brain development, and this decrease is likely responsible for the decreased sensitivity of brain tissue to apoptosis. However, the mechanism by which Apaf-1 expression is decreased remains elusive. In the present study, we found that four microRNAs (miR-23a/b and miR-27a/b) of miR-23a-27a-24 and miR-23b-27b-24 clusters play key roles in modulating the expression of Apaf-1. First, we found that miR-23a/b and miR-27a/b suppressed the expression of Apaf-1 in vitro. Interestingly, the expression of the miR-23-27-24 clusters in the mouse cortex gradually increased in a manner that was inversely correlated with the pattern of Apaf-1 expression. Second, hypoxic injuries during fetal distress caused reduced expression of the miR-23b and miR-27b that was inversely correlated with an elevation of Apaf-1 expression during neuronal apoptosis. Third, we made neuronal-specific transgenic mice and found that overexpressing the miR-23b and miR-27b in mouse neurons inhibited the neuronal apoptosis induced by intrauterine hypoxia. In conclusion, our results demonstrate, in central neural system, that miR-23a/b and miR-27a/b are endogenous inhibitory factors of Apaf-1 expression and regulate the sensitivity of neurons to apoptosis. Our findings may also have implications for the potential target role of microRNAs in the treatment of neuronal apoptosis-related diseases.
Highlights
apoptotic protease activating factor-1 (Apaf-1) is a component protein of the apoptosome
Immunohistochemistry (IHC) stain showed that the neuronal cells had little signal of Apaf-1 protein in the adult stage, whereas Apaf-1 protein was expressed in the neurons at the E18 stage (Figure 1c)
This differential expression of Apaf-1 is consistent with the decreases in susceptibility to apoptosis during mouse brain development that implies that expression of Apaf-1 might contribute to the susceptibility of neurons to apoptosis
Summary
Apaf-1 is a component protein of the apoptosome. In the intrinsic apoptosis pathway, cytochrome c is released from the mitochondria to the cytosol and binds to Apaf-1 protein. Previous studies have reported that the expression of Apaf-1 decreases in rat cerebral cortex during development, and this would explain the high sensitivity of the nervous system to apoptosis at the embryonic stage. The mechanism by which Apaf-1 expression is downregulated in the brain during development is still unknown. In microglia cells, hypoxia causes the upregulation of FasL expression and the downregulation of miR-21 expression during hypoxia-induced microglial activation.[24] Doeppner et al.[25] reported that miR-124 promotes neuronal survival under ischemic conditions via Usp14-dependent REST degradation. We tested the hypothesis that miRNAs may regulate Apaf-1 expression in the mouse cortex during development and in neurological diseases. We discovered that miRNAs regulate the sensitivity of neurons to apoptosis during development and hypoxiainduced brain injuries
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