A silencer element in the regulatory region of glutamine synthetase controls cell type-specific repression of gene induction by glucocorticoids

Glutamine synthetase is a key enzyme in the recycling of the neurotransmitt er glutamate, Expression of this enzyme is regulated by glucocorticoids, wh ich induce a high level of glutamine synthetase in neural but not in variou s non-neural tissues, This is despite the fact that non-neural cells expres s functional glucocorticoid receptor molecules capable of inducing other ta rget genes. Sequencing and functional analysis of the upstream region of th e glutamine synthetase gene identified, 5' to the glucocorticoid response e lement (GRE), a 21-base pair glutamine synthetase silencer element (GSSE), which showed considerable homology with the neural restrictive silencer ele ment NRSE. The GSSE was able to markedly repress the induction of gene tran scription by glucocorticoids in non-neural cells and in embryonic neural re tina. The repressive activity of the GSSE could be conferred on a heterolog ous GRE promoter and was orientation- and position-independent with respect to the transcriptional start site, but appeared to depend on a location pr oximal to the GRE, Gel-shift assays revealed that non-neural cells and cell s of early embryonic retina contain a high level of GSSE binding activity a nd that this level declines progressively with age. Our results suggest tha t the GSSE might be involved in the restriction of glutamine synthetase ind uction by glucocorticoids to differentiated neural tissues.