Abstract
Bicarbonate (HCO3−) is essential for preimplantation embryo development. However, the mechanism underlying the HCO3− transport into the embryo remains elusive. In the present study, we examined the possible involvement of Cl−/HCO3− exchanger in mediating HCO3− transport into the embryo. Our results showed that depletion of extracellular Cl−, even in the presence of HCO3−, suppressed embryo cleavage in a concentration-dependent manner. Cleavage-associated HCO3−-dependent events, including increase of intracellular pH, upregulation of miR-125b and downregulation of p53, also required Cl−. We further showed that Cl−/HCO3− exchanger solute carrier family 26 (SLC26) A3 and A6 were expressed at 2-cell through blastocyst stage. Blocking individual exchanger’s activity by inhibitors or gene knockdown differentially decreased embryo cleavage and inhibited HCO3−-dependent events, while inhibiting/knocking down both produced an additive effect to an extent similar to that observed when CFTR was inhibited. These results indicate the involvement of SLC26A3 and A6 in transporting HCO3− essential for embryo cleavage, possibly working in concert with CFTR through a Cl− recycling pathway. The present study sheds light into our understanding of molecular mechanisms regulating embryo cleavage by the female reproductive tract.
Highlights
After fertilization, mammalian embryos travel along the oviduct and make their way to the uterus before implantation
Consistent with previous study, embryo cleavage was reduced as the concentration of HCO3− in the TALP decreased, with less than 10% embryos develop into 4-cell stage when HCO3−-deficient TALP was used (Supplemental Fig. S1), confirming an essential role of HCO3− in the process of cleavage
The results showed that embryo cleavage decreased with decreasing Cl− concentrations in the medium, despite the presence of sufficient HCO3− (Fig. 1C,D)
Summary
Mammalian embryos travel along the oviduct and make their way to the uterus before implantation During this transit, the pre-implantation embryo undergoes cleavage, an important process producing more blastomere to enable differentiation, blastocyst formation, hatching and implantation[1,2]. CFTR knockout embryo showed reduced cleavage capacity and blastocyst formation in vitro and in vivo These results indicate an important role of CFTR in mediating HCO3− transport essential for preimplantation embryo development[1]. It remains to be resolved whether CFTR directly conducts HCO3− or acts as a Cl− channel working in parallel with a Cl−/HCO3− exchanger, thereby providing a recycling pathway for the Cl− that is necessary to operate the anion exchanger[12,13,14]. We undertook the present study to examine the possible involvement of Cl− and Cl−/HCO3− exchangers, the two SLC26A family members, in preimplantation embryo development
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