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

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

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Abstract

The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2-deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process.

Original languageEnglish (US)
Pages (from-to)2808-2824
Number of pages17
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015

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Nuclear Receptor Coactivator 2
Nuclear Receptor Coactivator 1
Pulmonary Surfactant-Associated Protein A
Mothers
Parturition
Platelet Activating Factor
Luteolysis
Embryonic Structures
Amniotic Fluid
Lung
1-Acylglycerophosphocholine O-Acyltransferase
Glycerophospholipids
1,2-Dipalmitoylphosphatidylcholine
Dinoprost
Surface-Active Agents
Progesterone
Up-Regulation
Gene Expression
Injections

ASJC Scopus subject areas

  • Medicine(all)

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Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. / Gao, Lu; Rabbitt, Elizabeth H.; Condon, Jennifer C.; Renthal, Nora E.; Johnston, John M.; Mitsche, Matthew A.; Chambon, Pierre; Xu, Jianming; O'Malley, Bert W.; Mendelson, Carole R.

In: Journal of Clinical Investigation, Vol. 125, No. 7, 01.07.2015, p. 2808-2824.

Research output: Contribution to journalArticle

Gao, L, Rabbitt, EH, Condon, JC, Renthal, NE, Johnston, JM, Mitsche, MA, Chambon, P, Xu, J, O'Malley, BW & Mendelson, CR 2015, 'Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition', Journal of Clinical Investigation, vol. 125, no. 7, pp. 2808-2824. https://doi.org/10.1172/JCI78544
Gao, Lu ; Rabbitt, Elizabeth H. ; Condon, Jennifer C. ; Renthal, Nora E. ; Johnston, John M. ; Mitsche, Matthew A. ; Chambon, Pierre ; Xu, Jianming ; O'Malley, Bert W. ; Mendelson, Carole R. / Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 7. pp. 2808-2824.
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abstract = "The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2-deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process.",
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