Fig. 6.

Model for iXCI regulation by the Rex1-Rnf12 axis. In a WT background, REX1 is expressed during the early stages after fertilization, but is degraded by RNF12. This leads to the upregulation of the paternal Xist allele, whilst its maternal counterpart is prevented from upregulation by an imprint. In Rnf12^−/+ embryos, the RNF12 level is sufficient to prevent REX1 stabilization, allowing for paternal Xist upregulation. However, this will result in inactivation of the paternal Rnf12 copy, which leads to an RNF12 KO situation, in its turn resulting in brief REX1 stabilization and preventing further paternal Xist upregulation. This feedback loop will prevent proper iXCI in trophoblast cells leading to Rnf12^−/+ embryo death. In Rnf12^−/− embryos, in the absence of RNF12, REX1 accumulates, preventing upregulation of Xist from the paternal allele. iXCI is absent and the embryos die. In Rnf12^−/−:Rex1^−/− embryos, the entire Rex1-Rnf12 axis is absent and iXCI can proceed normally as in WT embryos