| First Author | Zheng ZH | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 5 | Pages | e2214684120 |
| PubMed ID | 36693099 | Mgi Jnum | J:338573 |
| Mgi Id | MGI:7513800 | Doi | 10.1073/pnas.2214684120 |
| Citation | Zheng ZH, et al. (2023) METTL3 is essential for normal progesterone signaling during embryo implantation via m(6)A-mediated translation control of progesterone receptor. Proc Natl Acad Sci U S A 120(5):e2214684120 |
| abstractText | Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P(4)) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N(6)-methyladenosine (m(6)A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P(4) signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m(6)A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m(6)A modification. A luciferase assay revealed that the m(6)A modification in the 5' untranslated region (5'-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P(4) signaling during embryo implantation via m(6)A-mediated translation control of Pgr mRNA. |
