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 GR(Dermo1) mice, where the GR
gene was deleted within mesenchymal cells. Compared to their wild type littermates, GR(Dermo1) 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 GR(Dermo1) 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 GR(Dermo1) 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.