Molecular Regulation of Parturition: The Role of the Decidual Clock

Abstract

The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a “parturition cascade” exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a “placental clock.” We suggest that it is not a placental clock that regulates the timing of birth, but rather a “decidual clock.” Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock.

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturition

“…Importantly, GSK-J4 did not inhibit expression of 20α-hydroxysteroid dehydrogenase, the P4-catabolizing enzyme induced at term in the mouse ovary through the process of luteolysis (Supplemental Figure 7D), but nevertheless delayed delivery for about 24 hours ( Figure 5B, 98% pup viability; Supplemental Table 7). Conversely, P4 administration, with or without the vehicle for GSK-J4, delayed parturition 2 to 3 days (40%-50% pup viability), consistent with prior results and the idea that intrauterine processes are sufficient to drive labor induction in the presence of P4 (3,18). Delivery was strikingly delayed, however, in mice given both GSK-J4 and P4, with those still pregnant after E21.5 needing to be sacrificed due to maternal distress (0% pup viability).…”

“…Unexpectedly, H3K27me3 accrual in DSCs also silenced Ptgfr and Oxtr, which encode the prostaglandin PGF2α receptor (FP) and oxytocin receptor (OXTR) (6.4-and 10.8-fold lower expression in DSCs versus USCs, respectively; Supplemental Figure 3B and Supplemental Tables 1 and 3). This finding revealed an additional, directly anticontractile function for the gene-silencing program, since PGF2α and oxytocin are the primary hormones that drive uterine contraction during labor (3,15). On the other hand, the whole (i.e., unfractionated) E7.5 decidua as compared with whole, overlying myometrium (collectively termed dec>myo peaks), confirming their presence in early gestation implantation sites in vivo ( Figure 1, B and C, and Supplemental Tables 1 and 2).…”

“…For most of gestation, it assumes a relatively "quiescent" state while providing trophic and structural support to the placenta (1). At term, it enters an activated state that, through the production of inflammatory mediators, is thought to promote myometrial contractility and labor induction (2,3). The exact natures and molecular determinants of these 2 states remain largely undefined, however, which precludes a clear understanding of how the pregnant uterus transitions from quiescence to labor.…”

Mapping out p38MAPK

“…71 The decidua is a complex tissue 72, 73 comprised of stromal, leukocyte, glandular, and vascular elements. Each is likely to have its own regulation with regard to the mitogen activated kinases.…”

Seipin deficiency leads to defective parturition in mice†

“…Since ovarian hormones, especially P4 that is critical for decidualization and decidual clock, were proposed to regulate parturition [27], serum P4 and E2 levels were measured in the near-term D18.5 females. No significant differences in both P4 and E2 levels were observed between the D18.5 WT and Bscl2 −/− females (Fig.…”