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Discovery of a functional glucocorticoid receptor {beta}-isoform in zebrafish
In humans, two glucocorticoid receptor (GR) splice variants exist: GRα and GRβ, which are identical between amino acids 1–727 and then diverge. Whereas GRα (the canonical GR) acts as a ligand-activated transcription factor, GRβ does not bind traditional glucocorticoid agonists, lacks GRα’s transactivational activity, and acts as a dominant-negative inhibitor of GRα. It has been suggested that this receptor isoform is involved in the induction of glucocorticoid resistance in asthma patients. Unfortunately, a GR β-isoform has been detected in only humans, and therefore, an animal model for studies on this isoform is lacking. In the present study, we demonstrate that in zebrafish a GR isoform exists that diverges from the canonical zebrafish GR at the same position as human GRβ from human GRα. The zebrafish GR β-isoform acts as a dominant-negative inhibitor in reporter assays, and the extent of inhibition and the effective GRα/GRβ ratio is similar to studies performed with...
Show moreIn humans, two glucocorticoid receptor (GR) splice variants exist: GRα and GRβ, which are identical between amino acids 1–727 and then diverge. Whereas GRα (the canonical GR) acts as a ligand-activated transcription factor, GRβ does not bind traditional glucocorticoid agonists, lacks GRα’s transactivational activity, and acts as a dominant-negative inhibitor of GRα. It has been suggested that this receptor isoform is involved in the induction of glucocorticoid resistance in asthma patients. Unfortunately, a GR β-isoform has been detected in only humans, and therefore, an animal model for studies on this isoform is lacking. In the present study, we demonstrate that in zebrafish a GR isoform exists that diverges from the canonical zebrafish GR at the same position as human GRβ from human GRα. The zebrafish GR β-isoform acts as a dominant-negative inhibitor in reporter assays, and the extent of inhibition and the effective GRα/GRβ ratio is similar to studies performed with the human GR isoforms. In addition, the subcellular localization of zebrafish GRβ is similar to its human equivalent. Finally, expression levels of GRα and GRβ were determined in adult zebrafish tissues and at several developmental stages. Both receptor isoforms were detected throughout the body, and GRβ mRNA levels were relatively low compared with GRα mRNA levels, as in humans. Thus, for the first time, a GR β-isoform has been identified in a nonhuman animal species, shedding new light on the relevance of this GR splice variant and providing a versatile animal model for studies on the GR system.
- All authors
- Schaaf, M.J.M.; Champagne, D.; Laanen, I.H. van; Wijk, D.C. van; Meijer, A.H.; Meijer, O.C.; Spaink, H.P.; Richardson, M.K.
- Date
- 2008-04-01
- Journal
- Endocrinology
- Volume
- 149
- Issue
- 4
- Pages
- 1591 - 1599