Abstract

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.

Highlights

  • The successful establishment and maintenance of pregnancy relies on the elaborately regulated fetal-maternal crosstalk in the uterus as well as the coordinated adaptation of other maternal organs

  • Prolonged corpus luteum lifespan and sustainable progesterone production is a prerequisite for a successful pregnancy

  • In this study, utilizing a mouse model with uterine specific deletion of Notch2, which displayed decreased level of decidual prolactin member 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 maintenance

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Summary

Introduction

The successful establishment and maintenance of pregnancy relies on the elaborately regulated fetal-maternal crosstalk in the uterus as well as the coordinated adaptation of other maternal organs. Sustainable corpus luteum (CL) function and continuous progesterone (P4) secretion, which is pivotal to gestation maintenance, necessitates the maternal recognition of pregnancy as a prerequisite [1,2,3]. The cervical stimulation evokes the release of prolactin (Prl) from the anterior pituitary, which is able to support the CL for 10–12 days [4]. With embryonic development and placental formation, various lactogenic hormones secreted by placental trophoblast cells replace pituitary-derived Prl to support CL function until the final parturition [6]. Apart from pituitary Prl and trophoblast lactogens, decidual cells release factors belonging to the Prl family [7]. The functional relationship between pituitary Prl and these decidual-derived lactogens during pregnancy recognition and maintenance remains unclear

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