Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Gao, Lu; Rabbitt, Elizabeth; Condon, Jennifer C.; Renthal, Nora E.; Johnston, John M.; Mitsche, Matthew A.; Chambon, Pierre; Xu, Jianming; O’Malley, Bert W.; Mendelson, Carole R.

doi:10.1172/jci78544

Cited by 77 publications

(127 citation statements)

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“…Of relevance to the work by Gao et al, CRH (placentally or maternally derived) drives fetal production of cortisol, leading to fetal lung maturation and an increased concentration of lung surfactant in the amnion (24). Thus, future studies should lipid and is known to increase with lung development (16), was decreased in the fetal lungs of SRC-1/-2-deficient mice (15). As a result, levels of platelet-activating factor (PAF), an inflammatory phospholipid of amniotic fluid long thought to be important for parturition (17,18), were also decreased in both the fetal lungs and amniotic fluid.…”

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 93%

“…The results of this study corroborate earlier reports that injection of either SP-A (19) or PAF (18) into the amniotic fluid rescues delayed parturition phenotypes. Finally, Gao et al showed that many of the phenotypes of SRC-1/-2-deficient mice, including delayed birth and reduced expression of NF-κB, CAPs, and PGF 2 α, were all ameliorated by injection of either SP-A or PAF into the amnion, providing firm support that these proteins play an important role in the fetal signal that induces parturition (15).…”

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 99%

“…Gao et al report that pups born to WT mothers crossed with males that were deficient for both SRC-1 and SRC-2 had decreased SP-A in their lungs and amniotic fluid (15). Additionally, myometrial inflammation was suppressed, maternal progesterone was increased, and parturition was delayed by an average of approximately 38 hours -a considerable length of time for an animal with a total gestational length of 19.5 days.…”

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 99%

“…First, what are the additional transcriptional targets of SRC-1 and SRC-2 that contribute to the parturition phenotype reported? To eliminate the complication of studying transcription factors with multiple targets, the individual contributions of fetal SP-A and PAF to the onset of parturition could Gao et al went on to uncover the mechanisms by which these effects occurred (15). First, mothers of SRC-1/-2-deficient pups had a decreased inflammatory response and reduced expression of CAPs in the uterus.…”

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

“…Additionally, circulating levels of PGF 2 α were decreased, preventing luteolysis and the precipitous drop in maternal progesterone levels required for parturition. Next, Gao et al showed that levels of ovarian steroidogenic acute regulatory protein (StAR), which catalyzes the rate-limiting step of steroidogenesis and thus maintains progesterone levels during pregnancy, remained elevated in the mothers of the SRC-1/-2-deficient pups (15). As with the extent of delivery delay, the proportion of SRC-1/-2-deficient pups in each litter correlated with circulating progesterone levels in the mothers, emphasizing the fine-tuned interaction between fetal genotype and maternal physiology.…”

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

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Fetal-to-maternal signaling to initiate parturition

Reinl¹,

England²

2015

J. Clin. Invest.

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C o m m e n t a r y 2 5 6 9 jci.org Volume 125 Number 7July 2015 Fetal-to-maternal signaling to initiate parturition Erin L. Reinl and Sarah K. EnglandDepartment of Obstetrics and Gynecology -Basic Science Division, Washington University School of Medicine, St. Louis, Missouri, USA. Maternal control of gestational lengthWorldwide, 12% of babies are born preterm (<37 completed weeks of gestation), putting them at increased risk of mortality or lifelong disability. In fact, according to the World Health Organization, preterm birth is the leading cause of death in children under five years of age (1). Unfortunately, the ability to intervene to delay parturition (delivery) is limited. For example, tocolytics, which are used to acutely inhibit uterine contractions, are ineffective for long-term pregnancy maintenance. The successful development of effective interventions requires a more complete understanding of the molecular mechanisms that transition the uterus from a quiescent, noncontractile state during gestation to a highly activated, contractile state during parturition. The transition to activation and parturition is widely accepted as an inflammatory process (reviewed by Shynlova et al., ref. 2). Toward term, myometrial smooth muscle cells (MSMCs) produce chemo kines, such as CCL-2, that attract leukocytes into the myometrium (3). These leukocytes then produce a multitude of cyto kines (e.g., IL-8, TNF-α, IL-6, and IL-1β), thereby activating a feed-forward inflammation pathway (4). Within the MSMCs, cytokines activate the proinflammatory transcription factor NF-κB, which induces expression of several genes that promote parturition. These include receptors for the contraction inducers (uterotonins) oxytocin (5) and prostaglandin F 2 α (PGF 2 α) (6) and the prostaglandin synthase enzyme cyclooxygenase-2 (7). Additionally, NF-κB and mechanical stretch induce expression of the gap junction protein connexin-43 (8) and structural and contractile proteins (9, 10), known collectively as contractionassociated proteins (CAPs). The increased expression of CAPs enhances the sensitivity of the uterus to uterotonins, resulting in forceful and synchronous contractions. Coinciding with the increased NF-κB signaling at term is the downregulation of the antiinflammatory hormone progesterone, which is key for pregnancy maintenance. By lifting the effects of progesterone, either by a reduction in circulating progesterone via luteolysis (rodents) or by a functional withdrawal (humans), labor contractions can initiate. The importance of both progesterone withdrawal and inflammatory signaling is shown by the guaranteed induction of labor by treatment with the antiprogestin RU486 or by intrauterine injection of the endotoxin LPS. Does the fetus have a say in gestational length?In addition to the well-accepted role of the mother's physiology in triggering parturition, a signal from the growing fetus has long been thought to induce the cascade of events required for parturition. Previous work from Carole Mendelson's group (11) demonst...

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Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 93%

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 99%

Section: Does the Fetus Have A Say In Gestational Length?mentioning

confidence: 99%

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

Section: Remaining Questions and Future Directionsmentioning

confidence: 99%

See 3 more Smart Citations

Fetal-to-maternal signaling to initiate parturition

Reinl¹,

England²

2015

J. Clin. Invest.

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Arginase 1 does not affect RNA m6A methylation in mouse fetal lung

Sui,

Long

et al. 2024

Birth Defects Research

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BackgroundArginase 1 (Arg1) encodes a key enzyme that catalyzes the metabolism of arginine to ornithine and urea. In our recent study, we found that knockdown of Arg1 in the lungs of fetal mice induces apoptosis of epithelial cells and dramatically delays initiation of labor. As the most abundant internal mRNA modification, N6‐methyladenosine (m6A) has been found to play important roles in lung development and cellular differentiation. However, if the knockdown of Arg1 affects the RNA m6A modification in fetal lungs remains unknown.MethodsIn the current study, the RNA m6A levels and the expression of RNA m6A related enzymes were validated in 13.0 dpc fetal lungs that Arg1 was knocked down by adeno‐associated virus carrying Arg1‐shRNA, using western blot, immunofluorescence, and RT‐qPCR.ResultsNo statistical differences were found in the expression of methyltransferase, demethylases, and binding proteins in the fetal lungs between AAV‐shArg1‐injected mice and AAV‐2/9‐injected mice. Besides, there is no significant change of overall RNA m6A level in fetal lungs from AAV‐shArg1‐injected mice, compared with that from AAV‐2/9‐injected mice.ConclusionsThese results indicate that arginase 1 does not affect RNA m6A methylation in mouse fetal lung, and the mechanisms other than RNA m6A modification underlying the effects of Arg1 knockdown on the fetal lung development and their interaction with labor initiation need to be further explored.

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Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

et al. 2020

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Every year, 15 million pregnancies end prematurely, resulting in more than 1 million infant deaths and long-term health consequences for many children. The physiological processes of labour and birth involve essential roles for immune cells and proinflammatory cytokines in gestational tissues. There is compelling evidence that the mechanisms underlying spontaneous preterm birth are initiated when a premature and excessive inflammatory response is triggered by infection or other causes. Exposure to pro-inflammatory mediators is emerging as a major factor in the 'fetal inflammatory response syndrome' that often accompanies preterm birth, where unscheduled effects in fetal tissues interfere with normal development and predispose to neonatal morbidity. Toll-like receptors (TLRs) are critical upstream gatekeepers of inflammatory activation. TLR4 is prominently involved through its ability to sense and integrate signals from a range of microbial and endogenous triggers to provoke and perpetuate inflammation. Preclinical studies have identified TLR4 as an attractive pharmacological target to promote uterine quiescence and protect the fetus from inflammatory injury. Novel smallmolecule inhibitors of TLR4 signalling, specifically the non-opioid receptor antagonists (+)-naloxone and (+)-naltrexone, are proving highly effective in animal models for preventing preterm birth induced by bacterial mimetic LPS, heat-killed Escherichia coli, or the TLR4-dependent pro-inflammatory lipid, platelet-activating factor (PAF). Here, we summarise the rationale for targeting TLR4 as a master regulator of inflammation in fetal and gestational tissues, and the potential utility of TLR4 antagonists as candidates for preventative and therapeutic application in preterm delivery and fetal inflammatory injury.

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Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Cited by 77 publications

References 77 publications

Fetal-to-maternal signaling to initiate parturition

Fetal-to-maternal signaling to initiate parturition

Arginase 1 does not affect RNA m6A methylation in mouse fetal lung

Targeting Toll‐like receptor‐4 to tackle preterm birth and fetal inflammatory injury

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