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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,31]]},"abstract":"<jats:p>\n                    Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P\n                    <jats:sub>4<\/jats:sub>\n                    ) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that\n                    <jats:italic>\n                      N\n                      <jats:sup>6<\/jats:sup>\n                    <\/jats:italic>\n                    -methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P\n                    <jats:sub>4<\/jats:sub>\n                    \u00a0signaling. Conditional deletion of methyltransferase-like 3 (\n                    <jats:italic>Mettl3<\/jats:italic>\n                    ), encoding the m\n                    <jats:sup>6<\/jats:sup>\n                    A writer METTL3, in the female reproductive tract using a Cre mouse line with\n                    <jats:italic>Pgr<\/jats:italic>\n                    promoter (\n                    <jats:italic>Pgr-Cre<\/jats:italic>\n                    ) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of\n                    <jats:italic>Mettl3<\/jats:italic>\n                    null mice failed to respond to artificial decidualization. We further found that\n                    <jats:italic>Mettl3<\/jats:italic>\n                    deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that\n                    <jats:italic>Pgr<\/jats:italic>\n                    mRNA is a direct target for METTL3-mediated m\n                    <jats:sup>6<\/jats:sup>\n                    A modification. A luciferase assay revealed that the m\n                    <jats:sup>6<\/jats:sup>\n                    A modification in the 5\u2032 untranslated region (5\u2032-UTR) of\n                    <jats:italic>Pgr<\/jats:italic>\n                    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\u00a0vitro 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\n                    <jats:sub>4<\/jats:sub>\n                    signaling during embryo implantation via m\n                    <jats:sup>6<\/jats:sup>\n                    A-mediated translation control of\n                    <jats:italic>Pgr<\/jats:italic>\n                    mRNA.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2214684120","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T13:36:38Z","timestamp":1674567398000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":61,"title":["METTL3 is essential for normal progesterone signaling during embryo implantation via m\n                    <sup>6<\/sup>\n                    A-mediated translation control of progesterone 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