IN-VIVO EXPRESSION AND REGULATION OF ELK-1, A TARGET OF THE EXTRACELLULAR-REGULATED KINASE SIGNALING PATHWAY, IN THE ADULT-RAT BRAIN

The transcription factor Elk-1, a nuclear target of extracellular-regu lated kinases (ERKs), plays a pivotal role in immediate early gene ind uction by external stimuli. Notably, the degree of phosphorylation of Elk-1 is tightly correlated with the level of activation of transcript ion of c-fos by proliferative signals. No data yet indicate the role o f Elk-1 in the adult brain in vivo. To address this question, we have analyzed in the present work (1) Elk-1 mRNA and protein expression in the adult rat brain, and (2) the regulation of Elk-1 (i.e., its phosph orylation state) in an in vivo model of immediate early gene (IEG) ind uction: an electrical stimulation of the cerebral cortex leading to c- fos and zif268 mRNA induction in the striatum. Using in situ hybridiza tion, we show that Elk-1 mRNA is expressed in various brain structures of adult rat, and that this expression is exclusively neuronal. We de monstrate by immunocytochemistry using various specific Elk-1 antisera that the protein is not only nuclear (as shown previously in transien tly transfected cell lines) but is also present in soma, dendrites, an d axon terminals. On electrical stimulation of the glutamatergic corti costriatal pathway, we show a strict spatiotemporal correspondence amo ng ERK activation, Elk-1 phosphorylation, and IEG mRNA induction. Furt hermore, both activated proteins, analyzed by immunocytochemistry, are found in cytosolic and nuclear comparments of neuronal cells in the a ctivated area. Our data suggest that the ERK signaling pathway plays a n important role in regulating genes controlled by serum response elem ent sites via phosphorylation of Elk-1 in vivo.