Notch1 is crucial for decidualization and maintaining the first pregnancy in the mouse†

Abstract

The endometrium undergoes a pregnancy-delivery-repair cycle multiple times during the reproductive lifespan in females. Decidualization is one of the critical events for the success of this essential process. We have previously reported that Notch1 is essential for artificial decidualization in mice. However, in a natural pregnancy, the deletion of Notch1 (PgrCre/+Notch1f/f, or Notch1d/d) only affects female fertility in the first 30 days of a 6-month fertility test, but not the later stages. In the present study, we undertook a closer evaluation at the first pregnancy of these mice to attempt to understand this puzzling phenomenon. We observed a large number of pregnancy losses in Notch1d/d mice in their first pregnancy, which led to the subfertility observed in the first 30 days of the fertility test. We then demonstrated that the initial pregnancy loss is a consequence of impaired decidualization. Furthermore, we identified a group of genes that contribute to Notch1 regulated decidualization in a natural pregnancy. Gene ontogeny analysis showed that these differentially expressed genes in the natural pregnancy are involved in cell–cell and cell–matrix interactions, different from genes that have been previously identified from the artificial decidualization model, which contribute to cell proliferation and apoptosis. In summary, we determined that Notch1 is essential for normal decidualization in the mouse uterus only in the first pregnancy but not in subsequent ones.

Jagged1 regulates endometrial receptivity in both humans and mice

“…It demonstrates that NOTCH1 knockout specifically in the mouse uterus via Pgr-Cre generally affects genes enriched for cell-cell and cell-matrix interaction, cell adhesion, and plasma membrane function. 44 This is consistent with some of our findings where we noted gene expression levels in these pathways were significantly changed after Jag1 knockdown in the mouse uterine luminal epithelium.…”

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

“…Upon proteolytical cleavage, its intracellular domain is translocated into the nucleus to interact with the DNA-binding protein RBPJ and drive the transcription of downstream genes [20]. Deficiency of NOTCH1 or RBPJ in mice results in the abnormality of decidual reaction [21, 22]. In ESCs, melatonin lessened the expression of NOTCH1 and RBPJ, whereas adjunction of rNOTCH1 relieved the repression of melatonin on stromal differentiation, but this relief was impeded by NOTCH signaling pathway inhibitor DAPT, illustrating that regulation of melatonin on decidualization was mediated by NOTCH1 signaling pathway.…”