Research ReportMyocardin-related transcription factor-A promoting neuronal survival against apoptosis induced by hypoxia/ischemia

MRTF-A, known as one of the myocardin-related transcription factors, is widely found in newborn rat cortical or hippocampus neurons as well as in adult rat forebrain. Recent studies indicate that MRTF-A elevates SRF-driven transcription and enhances its stimulation by neurotrophic factor (BDNF). However, the mechanism underlying the contribution of the MRTF-A to neuronal survival is not completely understood. In this study, we investigated the effect of MRTF-A on neuronal apoptosis and its underlying mechanism. First of all, our study demonstrated that MRTF-A expression decreased obviously in rats' brains during the early period of cerebral ischemia-reperfusion. In order to estimate the effect of MRTF-A on neuronal apoptosis in vitro, we used an established experimental paradigm in which MRTF-A protected cortical neurons against both hypoxia-trophic deprivation and hydrogen peroxide-induced apoptosis. Obviously, over-expression of wild-type MRTF-A in cortical neurons inhibited apoptosis rate and enhanced anti-apoptotic gene-MCL-1. In contrast, co-expression of MRTF-A and the small interfering RNA of MRTF-A (siRNA) reversed the effect of neuroprotection and the upregulation on MCL-1 expression afforded by MRTF-A. Our study also determined whether the effect of MRTF-A up-regulating on MCL-1 expression is correlated to MRTF-A-enhancing CArG box transcription. The result showed that over-expression of wild-type MRTF-A upregulated the transcription activity of MCL reporter gene via driving the binding-domain CArG box in MCL-1 promoter, which was also reversed by co-expression of MRTF-A siRNA. In addition, we also found that BDNF neuroprotection on apoptosis induced by hypoxia-trophic withdrawal was not only inhibited by LY29004 and PD98059 but also partially blocked by transfection of dominant-negative MRTF-A in cortical neurons via enhancing the expression of anti-apoptotic gene-MCL-1, suggesting a downstream neuroprotective mechanism to BDNF neuroprotection on apoptosis.

Research Highlights► MRTF-A is involved in neuronal injury in vivo hypoxia/ischemia. ► MRTF-A inhibits apoptosis and up-regulates MCL-1 expression in vitro. ► MRTF-A enhances MCL-1 expression via triggering CArG box. ► MRTF-A-mediated transcription is involved in BDNF neuroprotection.