Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Abstract

While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

Effects of antenatal glucocorticoids on the developing brain

“…We have also found that the GR non-genomic pathway in NSPCs does not act independently, but rather indirectly modulates a genomic transcriptional response 77 . To understand whether the non-genomic GC pathway contributed to genomic action, we utilized Cav-1 knockout mice, interfering with non-genomic GR signaling.…”

“…Our results demonstrated that non-genomic action of lipid-raft associated GR was required for efficient phosphorylation of GR at a specific site, Serine 211. Furthermore, the GR transcriptome was altered in Cav-1 knockout mice, further suggesting that transcriptional output may be altered by Cav-1 interactions 77 . Site-specific phosphorylation of GR at serine 211 may contribute to differential transcriptional outcomes of sGC exposure of NSPCs as evidenced by the differential recruitment of phosphorylated GR to select target genes of wild type versus Cav-1 knockout mouse NSPCs.…”

“…One target gene whose expression and GR recruitment required crosstalk with the non-genomic GR signaling pathway was serum and glucocorticoid-regulated kinase (SGK-1), which regulates NSPC proliferation. Other affected gene networks included those responsible for organ development, axon guidance and protein degradation 77 . Pharmacological manipulation of these interacting pathways could provide better control of the diverse transcriptome activated by GCs.…”

Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors

“…It therefore readily engages ERα bound to caveolin-1, which serves as a scaffold for membrane-localized signalling molecules. Similarly, GR has been noted to localize to lipid rafts in association with caveolin-1 in neural progenitor and/or stem cells 64 . As noted above, classic VDR can also be found at caveolae 38 .…”

Role of mesenchymal stem cells on differentiation in steroid-induced avascular necrosis of the femoral head

“…At present, the exact pathological mechanism underlying SANFH is not fully known; however, numerous studies have indicated that a reduced number and the weakened activity of MSCs in the femoral neck and proximal femur may be among the underlying causes of SANFH (22)(23)(24). Due to the reduction in the number or the activity level of MSCs, their osteogenetic capacity decreases, and the lesion of necrotic bone cannot be effectively repaired, leading to the collapse of the femoral head (25). In the present study, following the routine culture of MSCs for 3 weeks, the number of adipocytes was found to be clearly detectable in the MSCs of the SANFH group compared with control and TANFH groups.…”