Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance. Author summary Progesterone secreted from the corpus luteum in the ovary is indispensable to preg-nancy maintenance in both rodents and humans. Therefore, prolonged corpus lute-um lifespan and sustainable progesterone production is a prerequisite for a success-ful pregnancy. In rodents, in addition to pituitary prolactin and placental lactogens, decidual derived factors have been presumed to possess luteotropic effects during the post-implantation stage. In this study, utilizing a mouse model with uterine spe-cific deletion of Notch2, which displayed decreased level of decidual prolactin mem-ber Prl8a2, combined with multiple approaches to interrupt the pituitary prolactin signal, we demonstrated that decidual derived Prl8a2 assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and mainte-nance. In addition, the expression of decidual Prl8a2 was under the direct control of the canonical Notch pathway. Together, we herein provide convincing evidence that decidual produced Prl8a2, modulated by uterine canonical Notch signaling, exhibits luteo-tropic functions and contributes to pregnancy maintenance.

Automated summary

This study demonstrated the essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Decidual derived Prl8a2 assists pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, contributing to pregnancy recognition and maintenance under the control of uterine canonical Notch signaling.