Glucocorticoid receptor isoform-specific regulation of development, circadian rhythm, and inflammation in mice

Abstract

Glucocorticoids are primary stress hormones, and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced froma single gene by alternative translation initiation; however, the role individual isoforms play in tissue-specific responses to glucocorticoids is unknown. We have generated knockinmice that exclusively express themost active receptor isoform,GR-C3.GR-C3 knockinmice die at birthdue to respiratory distress.Microarray analysis of fibroblasts fromwild-type andGR-C3 mice indicated thatmost genes regulated by GR-C3 were unique to this isoform. Antenatal glucocorticoid administration rescued GR-C3 knockin mice fromneonatal death.Dual-energyX-ray absorptiometry revealed nomajor alterations in body composition for rescued knockinmice.Rescued female, but notmale,GR-C3mice exhibited increasedwheel running activity in the light portion of the day. LPS administration induced prematuremortality in rescuedGR-C3 knockinmice, and gene expression studies revealed a deficiency in the ability of GR-C3 to repress a large cohort of immune and inflammatory response genes. These findings demonstrate that specific GR translational isoforms can influence development, circadian rhythm, and inflammation through the regulation of distinct gene networks.