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

J Clin Invest. 2015 Jul 1;125(7):2808-24. doi: 10.1172/JCI78544. Epub 2015 Jun 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Acylglycerophosphocholine O-Acyltransferase / deficiency
  • 1-Acylglycerophosphocholine O-Acyltransferase / genetics
  • Animals
  • Female
  • Fetal Organ Maturity
  • Heterozygote
  • Lung / embryology
  • Lung / physiology
  • Luteolysis
  • Male
  • Maternal-Fetal Exchange / genetics
  • Maternal-Fetal Exchange / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Nuclear Receptor Coactivator 1 / deficiency
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / physiology*
  • Nuclear Receptor Coactivator 2 / deficiency
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / physiology*
  • Parturition / physiology*
  • Platelet Activating Factor / deficiency
  • Pregnancy
  • Promoter Regions, Genetic
  • Pulmonary Surfactant-Associated Protein A / deficiency
  • Signal Transduction
  • Transcriptional Activation
  • Uterus / physiology

Substances

  • Ncoa2 protein, mouse
  • Nuclear Receptor Coactivator 2
  • Platelet Activating Factor
  • Pulmonary Surfactant-Associated Protein A
  • 1-Acylglycerophosphocholine O-Acyltransferase
  • Lpcat1 protein, mouse
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1