Disruption of β-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice

In this study, the role of β-arrestin 1 and β-arrestin 2 in fetal lung and liver development was examined using Arrb1−/−Arrb2−/− mouse embryos. β-Arrestin 1/2 dual-null mice died shortly after birth and morphological examination revealed an obvious pulmonary hypoplasia and severe hepatic impairment. Western blot analysis demonstrated that GR protein levels in Arrb1−/−Arrb2−/− lung and liver tissues were significantly decreased compared to wild type embryos. Expression of GR proteins was confirmed in the nuclei of type II pneumocytes of 18.5 day embryos (E18.5) by immunofluorescence. The production of hepatic glucose and mRNA level of gluconeogenic enzymes were dramatically reduced in E18.5 Arrb1−/−Arrb2−/− liver. These results suggest that GR is an important downstream effector of the β-arrestin signaling pathway involved in regulation of lung and liver development. However, no obvious changes in GR expression following in vitro modulation of β-arrestin 1/2 indicated the existence of an indirect regulatory relationship between GR and the β-arrestin signaling pathway.

► The role of β-arrestin 1/2 in fetal lung and liver development was examined.
► Morphological examination revealed a pulmonary hypoplasia and hepatic impairment in Arrb1−/−Arrb2−/− mice.
► GR expression was confirmed in type II cells of E18.5 lung and decreased in Arrb1−/−Arrb2−/− lung.
► The decrease of GR in E18.5 Arrb1−/−Arrb2−/− liver leaded to reduction of the hepatic glucose and gluconeogenic enzymes.
► GR and the β-arrestin signaling pathway might have an indirect regulatory relationship.