Roles of the Rlim-Rex1 axis during X chromosome inactivation in mice

Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2313200120. doi: 10.1073/pnas.2313200120. Epub 2023 Dec 19.


In female mice, the gene dosage from X chromosomes is adjusted by a process called X chromosome inactivation (XCI) that occurs in two steps. An imprinted form of XCI (iXCI) that silences the paternally inherited X chromosome (Xp) is initiated at the 2- to 4-cell stages. As extraembryonic cells including trophoblasts keep the Xp silenced, epiblast cells that give rise to the embryo proper reactivate the Xp and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI require the lncRNA Xist, which is expressed from the X to be inactivated. The X-linked E3 ubiquitin ligase Rlim (Rnf12) in conjunction with its target protein Rex1 (Zfp42), a critical repressor of Xist, have emerged as major regulators of iXCI. However, their roles in rXCI remain controversial. Investigating early mouse development, we show that the Rlim-Rex1 axis is active in pre-implantation embryos. Upon implantation Rex1 levels are downregulated independently of Rlim specifically in epiblast cells. These results provide a conceptual framework of how the functional dynamics between Rlim and Rex1 ensures regulation of iXCI but not rXCI in female mice.

Keywords: Rex1/Zfp42; Rlim/Rnf12; X chromosome inactivation; extraembryonic ectoderm; implantation.

MeSH terms

  • Animals
  • Embryo, Mammalian / metabolism
  • Female
  • Mice
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • X Chromosome / genetics
  • X Chromosome / metabolism
  • X Chromosome Inactivation* / genetics


  • Rlim protein, mouse
  • RNA, Long Noncoding
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • PREX1 protein, mouse