Abstract
As a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, the glucocorticoid receptor (GR) is essential for normal embryonic development. To date, the role of mesenchymal glucocorticoid signaling during development has not been fully elucidated. In the present study, we investigated the role of the GR during embryogenesis specifically in mesenchymal tissues. To this aim, we crossed GRflox mice with Dermo1-Cre mice to generate GRDermo1 mice, where the GR gene was deleted within mesenchymal cells. Compared to their wild type littermates, GRDermo1 mice displayed severe pulmonary atelectasis, defects in abdominal wall formation resulting in intestinal herniation, abnormal extracellular matrix synthesis in connective tissues and high postnatal lethality. Lungs of GRDermo1 mice failed to progress from the canalicular to saccular stage, as evidenced by the presence of immature air sacs, thickened interstitial mesenchyme and an underdeveloped vascular network between E17.5 and E18.5. Furthermore, myofibroblasts and vascular smooth muscle cells, although present in normal numbers in GRDermo1 animals, were characterized by significantly reduced elastin synthesis, whilst epithelial lining cells of the immature saccules were poorly differentiated. A marked reduction in normal elastin and collagen deposits were also observed in connective tissues adjacent to the umbilical hernia. This study demonstrates that eliminating the GR in cells of the mesenchymal lineage results in marked effects on interstitial fibroblast function, including a significant decrease in elastin synthesis. This results in lung atelectasis and postnatal lethality, as well as additional and hitherto unrecognized developmental defects in abdominal wall formation. In addition, altered glucocorticoid signaling in the mesenchyme attenuates normal lung epithelial differentiation.
Highlights
As a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, the glucocorticoid receptor (GR) appears to play an essential role during development [1,2,3,4]
These findings suggested that deletion of the mesenchymal GR leads to neonatal lethality due to abnormal lung development
Epithelia As glucocorticoids have been shown to play a key role in the differentiation of epithelia in fetal lung, we examined downstream glucocorticoid-signaling in pulmonary tissue of GRDermo1 mice by measuring the expression of the glucocorticoid-induced leucine zipper (GILZ) [10,11]
Summary
As a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, the glucocorticoid receptor (GR) appears to play an essential role during development [1,2,3,4]. The lungs were shown to be one of the most important glucocorticoid target tissues during embryogenesis, with lung atelectasis resulting in post natal lethality in the global GR null mouse [4]. In these animals, a generalized increase in cellular proliferation was observed throughout the lung, whilst apoptosis remained normal [7]. Bird et al hypothesized that this increase in cellular proliferation contributes to mesenchymal thickening, resulting in lung atelectasis Supporting these findings, the expression of the GR was shown to be markedly elevated during the canalicular and saccular stages of lung development in both human and animal models [4,8,9,10,11]. The Dermo1-Cre strain was created by a homologous knock-in of Cre into the Dermo gene locus, which allows for more precise expression of
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