The glucocorticoid signaling pathway is responsive to a considerable number of internal and external signals and can therefore establish diverse patterns of gene expression. A glial‐specific pattern, for example, is shown by the glucocorticoid‐inducible gene glutamine synthetase. The enzyme is expressed at a particularly high level in glial cells, where it catalyzes the recycling of the neurotransmitter glutamate, and at a low level in most other cells, for housekeeping duties. Glial specificity of glutamine synthetase induction is achieved by the use of positive and negative regulatory elements, a glucocorticoid response element and a neural restrictive silencer element. Though not glial specific by themselves, these elements may establish a glial‐specific pattern of expression through their mutual activity and their combined effect. The inductive activity of glucocorticoids is markedly repressed by the c‐Jun protein, which is expressed at relatively high levels in proliferating glial cells. The signaling pathway of c‐Jun is activated by the disruption of glia–neuron cell contacts, by transformation with v‐src, and in proliferating retinal cells of early embryonic ages. The c‐Jun protein inhibits the transcriptional activity of the glucocorticoid receptor and thus represses glutamine synthetase expression. This repressive mechanism might also affect the ability of glial cells to cope with glutamate neurotoxicity in injured tissues. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 513–527, 1999

Glutamine synthetase is a key enzyme in the recycling of the neurotransmitter glutamate. Expression of this enzyme is regulated by glucocorticoids, which induce a high level of glutamine synthetase in neural but not in various non-neural tissues. This is despite the fact that non-neural cells express functional glucocorticoid receptor molecules capable of inducing other target genes. Sequencing and functional analysis of the upstream region of the glutamine synthetase gene identified, 5 to the glucocorticoid response element (GRE), a 21-base pair glutamine synthetase silencer element (GSSE), which showed considerable homology with the neural restrictive silencer element NRSE. The GSSE was able to markedly repress the induction of gene transcription by glucocorticoids in non-neural cells and in embryonic neural retina. The repressive activity of the GSSE could be conferred on a heterologous GRE promoter and was orientation-and position-independent with respect to the transcriptional start site, but appeared to depend on a location proximal to the GRE. Gel-shift assays revealed that non-neural cells and cells of early embryonic retina contain a high level of GSSE binding activity and that this level declines progressively with age. Our results suggest that the GSSE might be involved in the restriction of glutamine synthetase induction by glucocorticoids to differentiated neural tissues.Glutamine synthetase (GS 1 ; L-glutamate:ammonia ligase (ADP-forming); EC 6.3.1.2) is a "housekeeping" enzyme that is expressed at a particularly high level in neural tissues (1, 2). High levels of GS expression are restricted to glial cells (1,(3)(4)(5) and are essential for the recycling of the neurotransmitter glutamate. Synaptically released glutamate is taken up into glial cells, where it is converted by GS into glutamine, which re-enters the neurons and is hydrolyzed by glutaminase to form glutamate again (6, 7). In this way, the neurotransmitter pool is replenished and glutamate neurotoxicity is prevented.Studies in the chicken neural retina showed that GS expression is regulated by systemic glucocorticoids, which induce in this tissue a very high level of GS by directly stimulating the transcription of the gene (8 -10). The ability of glucocorticoids to induce GS expression is developmentally controlled. Glucocorticoids can induce a high level of GS expression in neural retina at late embryonic ages, but not in early embryonic retina (2, 11-13). The direct involvement of glucocorticoids in the control of GS gene transcription is evidenced by the nuclear run-on transcription assay, as well as by the finding that the upstream region of the GS gene contains a glucocorticoid response element (GRE) that can bind the glucocorticoid receptor protein and confer responsiveness to glucocorticoids on an attached reporter gene (8 -10, 14, 15). This mode of regulation, which is dependent on the presence of active glucocorticoid receptor molecules, explains the cell type specificity of GS expression in the neural retina; GS expression is ...

No abstract