A role of C/EBPa in pre-implantation development?

The observation that a pulse of C/EBPa drives the highly efficient B cell to iPS cell reprogramming induced by the Yamanaka factors raised the possibility that this reflects a role of C/EBPa during the specification of pluripotent cells in the early embryo.

The Il6 pathway is required for cell reprogramming

Work by the laboratories of Helen Blauand Manuel Serrano has shown that the IL6 pathway, which has been associated with cellular senescence and inflammation, is crucial for somatic cell reprogramming both in vitro and in vivo. Likewise, a blocking anti Il6 antibody almost completely inhibited C/EBPa enhanced B cell to iPSC reprogramming. In our reprogramming system we find that both Il6 and Il6r become upregulated and C/EBPa binds to the promoter of these genes. These findings suggest that the Il6 pathway is directly regulated by the factor.

Cebpais expressed in early embryos

To explore the possibility that this recapitulates an early developmental process we examined published RNAseq data of mouse embryo development and found that Cebpa becomes expressed at the late 2C stage,peaks at the 8 cell stage, becomes down regulated at the 16 cells stage and is again expressed in the trophectoderm but not in the inner cell mass (pluripotent) cells of the blastocyst. Staining of different developmental stages with antibodies against the factor showed that the factors is also expressed at the protein level and localizes to the nucleus.

An antibody that blocks Il6 delays early embryo development

Similar RNA expression dynamics during early embryo development as for Cebpa were detected for the Il6 and Il6r genes. We therefore tested the effect of the Il6 blocking antibody on developing mouse embryos in culture. Intriguingly, treatment with the antibody delayed the morula-blastocyst transition, indicating that the IL6 pathway is functional in early embryos. These findings suggest that IL6 signaling is not only required for the reprogramming of somatic into pluripotent cells but also plays a role in pre-implantation mouse embryos. Current work addresses the hypothesis that C/EBPa directly drives the expression of the IL6 pathway during early mouse embryo development and that a knock-down of the factor delays the morula to blastocyst transition.

Ongoing work by Marcos Plana and Carolina Segura