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
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
View: Text | PDF
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

×

Figure 6

Delayed parturition and decreased NF-κB activation and expression of Cx43 and Oxtr in SRC-1/-2 dhet females bred to SRC-1/-2 dhet males are rescued by i.a. injection of SP-A or PAF at 17.5 dpc.

Options: View larger image (or click on image) Download as PowerPoint
Delayed parturition and decreased NF-κB activation and expression of Cx4...
(A) Gestation length of SRC-1/-2 dhet females × SRC-1/-2 dhet males injected i.a. at 17.5 dpc with PBS (n = 9), SP-A (n = 10), or PAF (n = 10). (B and C) Nuclear translocation of NF-κB subunits p65 and p50 in 18.5 dpc myometrial tissues of WT females × WT males (uninjected, n = 3) or SRC-1/-2 dhet females × SRC-1/-2 dhet males injected i.a. with PBS (n = 3), SP-A (n = 3), or PAF (n = 4) at 17.5 dpc. The same immunoblots of loading controls, histone H3, and GAPDH are shown for nuclear and cytoplasmic proteins, respectively, since p65 and p50 were probed on the same respective blots. (D) Cx43 mRNA levels (n = 6 per group) and (E) protein levels (n = 3 for WT, PBS, and SP-A; n = 4 for PAF) in myometrium. The same immunoblot of β-actin was used for normalization of OXTR (G), which was probed on the same blot. (F) Oxtr mRNA (n = 6 per group) and (G) protein (n = 3 for WT, PBS, and SP-A; n = 4 for PAF) in myometrium. Data are the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with WT; #P < 0.05, ##P < 0.01, ###P < 0.001 compared with PBS injection (ANOVA).