Endocrine Abstracts

Glucocorticoid signalling is essential during embryonic lung development, with both the global and epithelial glucocorticoid receptor (GR) null mice presenting with lung atelectasis and post natal lethality. In this study, we examined the role of glucocorticoid signalling within mesenchymal tissues. To study the role of the GR in mesenchymal tissues during embryogenesis we crossed GRflox mice with Dermo1-Cre mice to generate GR^Dermo1 mice, where the GR gene was conditionally deleted within mesenchymal cells. Organ development between E14.5 through to birth was determined by histological staining and MRI performed at E18.5. Specific mesenchymal cell populations were assessed by immunohistochemistry and quantitative RT-PCR. GR^Dermo1 mice displayed severe pulmonary atelectasis, defective abdominal wall formation and postnatal lethality. GR^Dermo1 mice failed to progress from the canalicular to saccular stage of lung development, evidenced by the presence of immature air sacs, thickened interstitial mesenchyme and an underdeveloped vascular network between E14.5 and E18.5 (lung tissue to alveolar space; GR^Dermo1, 90.3% vs WT, 79.6%, P<0.001). Interstitial fibroblast numbers were expanded within GR^Dermo1 mice compared to WT littermates (50.1 vs 21.1 cells/ 50 μm²; P<0.005). However, myofibroblasts, vascular smooth muscle and endothelial cells were shown to be present in normal numbers. Analysis of their functionality revealed that myofibroblasts from GR^Dermo1 mice possessed significantly reduced elastin synthesis. In contrast epithelial lining cells of immature saccules were poorly differentiated. Reduced elastin and collagen deposits were also noted 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 signalling in the mesenchyme indirectly attenuates normal lung epithelial differentiation.

Declaration of funding

National Health & Medical Research Council, Australia, Project Grant 632819 to MJS and HZ. RSH received support from Arthritis Research UK (ref no 19552).