title: Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition.
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.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Condon
authors.forename: Nora E
authors.initials: NE
authors.lastname: Renthal
authors.forename: John M
authors.initials: JM
authors.lastname: Johnston
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mitsche
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Carole R
authors.initials: CR
authors.lastname: Mendelson
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D005260:Female; D005325:Fetal Organ Maturity; D006579:Heterozygote; D008168:Lung / Q000196:embryology / Q000502:physiology; D003341:Luteolysis; D008297:Male; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D056920:Nuclear Receptor Coactivator 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051958:Nuclear Receptor Coactivator 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D036801:Parturition / Q000502:physiology*; D010972:Platelet Activating Factor / Q000172:deficiency; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency; D015398:Signal Transduction; D015533:Transcriptional Activation; D014599:Uterus / Q000502:physiology
chemical_list: C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D010972:Platelet Activating Factor; D037662:Pulmonary Surfactant-Associated Protein A; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1