Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition
Lu Gao, … , Bert W. O’Malley, Carole R. Mendelson
Lu Gao, … , Bert W. O’Malley, Carole R. Mendelson
Published July 1, 2015; First published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2808-2824. https://doi.org/10.1172/JCI78544.
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Research Article Reproductive biology

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

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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Figure 1

Delayed parturition in SRC-1/-2 dhet female × SRC-1/-2 dhet male and WT female × 1-KO/2-het male is associated with reduced SP-A expression in lungs of SRC-1/-2 double-deficient fetuses.

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Delayed parturition in SRC-1/-2 dhet female × SRC-1/-2 dhet male and WT ...
(A) Genotypes resulting from crosses of SRC-1/2 dhet females × SRC-1/2 dhet males and gestation length of pregnancies resulting from these double heterozygous crosses. (B) Gestation length of WT females × WT males (n = 13), SRC-1–/– females × SRC-1–/– males (n = 16), SRC-2+/– females × SRC-2+/– males (n = 10), SRC-1/-2 dhet females × SRC-1/-2 dhet males (n = 49), and WT females × 1-KO/2-het males (n = 25). (C) Gestation length of SRC-1/-2 dhet females × SRC-1/-2 dhet males is positively correlated with proportion of SRC-1 SRC-2 double-deficient pups. (D) SP-A mRNA in lungs of WT (n = 4), SRC-1/-2 dhet (dhet; n = 14), SRC-1/-2 dKO (dKO; n = 3), 1-KO/2-het (KO/het; n = 6), SRC-1 het/SRC-2 KO (het/KO; n = 6), SRC-1 KO/SRC-2 WT (KO/WT; n = 3), SRC-1 het/SRC-2 WT (het/WT; n = 13), and SRC-1 WT/SRC-2 het (WT/het; n = 4) fetuses at 18.5 dpc from matings of SRC-1/-2 dhet females × SRC-1/-2 dhet males. (E) SP-A protein in 18.5 dpc fetal lung from SRC-1/-2 dhet females × SRC-1/-2 dhet males. Representative immunoblot of SP-A protein according to genotype, and data from scans of SP-A immunoblots normalized to β-actin for WT (n = 6), SRC-1/-2 dhet (n = 6), and SRC-1/-2 dKO (n = 4) fetuses. (F) SP-A protein in AF surrounding WT and SRC-1/-2–deficient fetuses. In the representative immunoblot, the first 3 lanes were run on same gel but were noncontiguous with the remaining 5 lanes (divided by the black line). Combined data from scans of immunoblots of SP-A in AF surrounding WT (n = 5), dhet (n = 14), dKO (n = 3), KO/het (n = 6), het/KO (n = 6), KO/WT (n = 3), het/WT (n = 13), and WT/het (n = 4) fetuses. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA).