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The mechanisms that lead to the initiation of parturition are incompletely defined. Parturition timing is mediated by signals from both mother and fetus. Our previous findings using mice that were double-deficient in steroid receptor coactivators (Src)1 and 2 (Src-1/-2d/d) suggest that the fetus signals its mother when it is ready to be born through fetal lung production of surfactant components, surfactant protein A (SP-A) and platelet-activating factor (PAF). Notably, mice that are double knockout for Src-1/-2 die at birth of respiratory distress, due to decreased surfactant lipoprotein production. Intriguingly, we observed that wild-type (WT) mothers carrying Src-1/-2d/d fetuses manifested a ~38 h delay in parturition compared to WT mothers carrying WT fetuses. This was associated with decreased production of SP-A and PAF by the Src-1/-2d/d fetal lungs. Our findings suggested that these effects of Src-1/-2d/d were caused by impaired glucocorticoid receptor (GR) transcriptional activity in fetal lung cells. To identify other genes in fetal lung that were affected by Src-1/-2d/d, we conducted RNA-seq analysis of lungs from 18.5 days post-coitum Src-1/-2d/dvs. WT fetuses. We observed that one of the genes most highly downregulated in Src-1/-2d/d fetal lungs was 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 catalyzes the conversion of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, which are ligands for the glucocorticoid receptor (GR). We validated the RNA-seq results by RT-qPCR and immunoblotting and observed a striking reduction of 11β-HSD1 mRNA and protein in lungs of Src-1/2d/d fetuses, compared to WT. Others observed that glucocorticoids potently increased 11β-HSD1 expression in various cell types via activation of transcription factors C/EBPα and C/EBPβ, providing a potential positive feed-forward loop. Notably, we observed that C/EBPα and C/EBPβ mRNA and protein were markedly reduced in Src-1/-2d/d fetal lungs, compared to WT. Deletion of the Cebpa gene in respiratory epithelium of fetal mice caused respiratory failure at birth due to surfactant lipid and protein deficiency. This was associated with increased expression of TGF-β2, which inhibits fetal lung maturation. Notably, we observed that expression of TGF-β2 and TGF-β3 were increased in Src-1/-2d/d fetal lungs. Thus, impaired lung development, surfactant synthesis and delayed parturition in Src-1/-2d/d fetuses are likely caused by decreased 11β-HSD1 and GR signaling, resulting in decreased C/EBPα/β expression and increased TGF-β signaling.

MON-005 Inhibition of Glucocorticoid Signaling in SRC-1/-2 Double-Deficient Mice Results in Impaired Lung Maturation and Delayed Parturition