Glucocorticoids regulate a wide range of systems in vertebrate organisms, and their effects are mediated by the
glucocorticoid receptor (GR). The responsiveness to
glucocorticoids differs largely between individuals. Resistance to
glucocorticoids is an important medical problem, since it limits the efficacy of
glucocorticoids when they are used to treat immune-related diseases like
asthma and
rheumatoid arthritis.
Glucocorticoid resistance also contributes to the pathogenesis of other diseases, like major depression because of the decreased negative feedback on the hypothalamic pituitary adrenal axis. In this review, we present the zebrafish as an excellent in vivo model system to study
glucocorticoid resistance. First, the zebrafish is the only non-primate animal model in which a beta-
isoform of GR occurs, which is a splice variant with dominant-negative activity. Zebrafish are easily genetically modified, so the expression of
GRbeta can be varied, creating an in vivo model for
GRbeta-induced
glucocorticoid resistance. Second, by performing a forward-genetic screen using the
glucocorticoid-induced decrease in
POMC expression in the pituitary gland as a readout, several zebrafish mutants have been obtained which appear to be resistant to
glucocorticoid treatment. We present here two types of in vivo models for studying
glucocorticoid resistance, that will be used to study the molecular mechanism of
glucocorticoid signaling and resistance. Finally these models will be used to screen for small molecules that can alleviate
glucocorticoid resistance.