CFTR mediates bicarbonate-dependent activation of miR-125b in preimplantation embryo development

Although HCO 3 is known to be required for early embryo development, its exact role remains elusive. Here we report that HCO 3 acts as an environmental cue in regulating miR-125b expression through CFTR-mediated influx during preimplantation embryo development. The results show that the effect of HCO 3 on preimplantation embryo development can be suppressed by interfering the function of a HCO 3-conducting channel, CFTR, by a specific inhibitor or gene knockout. Removal of extracellular HCO 3 or inhibition of CFTR reduces miR-125b expression in 2 cell-stage mouse embryos. Knockdown of miR-125b mimics the effect of HCO 3 removal and CFTR inhibition, while injection of miR-125b precursor reverses it. Downregulation of miR-125b upregulates p53 cascade in both human and mouse embryos. The activation of miR-125b is shown to be mediated by sAC/PKA-dependent nuclear shuttling of NF-κB. These results have revealed a critical role of CFTR in signal transduction linking the environmental HCO 3 to activation of miR-125b during preimplantation embryo development and indicated the importance of ion channels in regulation of miRNAs.