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.
The Chinese University of Hong Kong - Zhejiang University Joint Laboratory for Human Reproduction and Related Diseases, Hong Kong, China.
Yong Chao
YC
Lu
Hui
H
Chen
Kin Lam
KL
Fok
Lai Ling
LL
Tsang
Mei Kuen
MK
Yu
Xiao Hu
XH
Zhang
Jing
J
Chen
Xiaohua
X
Jiang
Yiu Wa
YW
Chung
Alvin Chun Hang
AC
Ma
Anskar Yu Hung
AY
Leung
He Feng
HF
Huang
Hsiao Chang
HC
Chan
D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D001639:Bicarbonates; D007473:Ion Channels; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D019005:Cystic Fibrosis Transmembrane Conductance Regulator