Deletion of Prl7d1 causes placental defects at mid‐pregnancy in mice

Abstract

Prolactin family 7, subfamily d, member 1 (Prl7d1), a member of the expanding prolactin family, is mainly expressed in the placental junctional zone (including trophoblast giant cells and spongiotrophoblast cells) with peak expression observed at 12 days postcoitum (dpc) in mice. Previous studies have shown that PRL7D1 is a key mediator of angiogenesis in vitro; however, its physiological roles in placental development in vivo have not been characterized. To address this issue, we deleted Prl7d1 in mice and demonstrated that its absence results in reduced litter size and fertility. Histologically, Prl7d1 mutants exhibited striking placental abnormalities at 12.5 dpc, including a reduction in the proportion of labyrinth layers and a significant increase in decidual natural killer cells, glycogen trophoblasts, and trophoblast giant cells in the junctional zone. Moreover, placentas from Prl7d1‐null mice displayed a thickened decidual spiral artery. Notably, these negative effects were more pronounced in male fetuses. Further RNA‐sequencing analysis showed that Prl7d1 deletion results in significant differences in the placental transcriptome profile between the two sexes of fetuses. Together, this study demonstrates that Prl7d1 possesses antiangiogenic properties in deciduas and inhibits the development of junctional zone, which potentially alters the functional capacity of the placenta to support optimal fetal growth. Moreover, of note, the role of Prl7d1 in the placenta is regulated in a fetal sex‐specific manner.

The Influence of the Prolactins on the Development of the Uterus in Neonatal Mice

“…Previous studies have shown that Prl −/− systemic knockout of Prl can affect the estrous cycle, leading to abnormal mammary gland development and infertility in female mice ( 24 ). Prl7d1 −/− knockout can lead to the thickening of the placental decidual spiral artery, resulting in reduced litter size and decreased fertility ( 25 , 44 ). Prlr −/− knockout can lead to female infertility and failure of progesterone production by the corpus luteum of the ovary in mice, leading to pregnancy failure ( 45 ).…”

“…Prl1a1 knockout results in female mice infertility ( 24 ). Prl7d1 −/− knockout results in smaller litter size ( 25 ). In adult mice, rabbits, and pigs, hyperprolactinemia stimulates uterine glandular hypertrophy ( 26 ).…”

Comparative single cell analysis reveals complex patterns of cell type and cell signaling innovations at the fetal-maternal interface

“…A progenitor invasive trophoblast subpopulation (Mm_TGC-Prog) was enriched for Ascl2, Ldoc1, and Prdm1 36 , interstitially invasive glycogen trophoblast (Mm_TGC_Gly) was enriched in Arid3a , and endovascularly invasive spiral artery-remodeling giant cells (Mm_TGC-SpA) expressed the prolactins Prl2a1 and Prl7b1 . Lastly, noninvasive sinusoidal giant cells (Mm_TGC_S) were marked by Prl2c2, Prl3b1 , and Prl7d1 37 , and canal giant cells (Mm_TGC_C) were marked by Hand1 and Prl2c1 .…”

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders

“…Targeted deletion of the prolactin-related genes Prl4a1 [54] and Prl7b1 [55] have minor effects on the placenta under normal conditions but major effects in response to stressors such as hypoxia. Targeted deletion of Prl7d1 results in a reduction of the labyrinth and gain in the junctional zone with a sex specific increase in the number of glycogen cells in the male placenta [56]. Placental hormone levels can be manipulated en mass through the genetic modification of imprinted genes which regulate the number of placental cells expressing hormones [57].…”