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In the mammalian hippocampus, changes in the expression of immediate early genes (lEGs) is thought to contribute to long term plastic changes in neurons brought about by learning tasks and high frequency stimulation of synapses. The phosphatase calcineurin has emerged as an important negative regulator of hippocampus-dependent learning and long term potentiation. Here we investigated the possibility that the constraining action of calcineurin on hippocampal plasticity is mediated in part by regulation of gene expression through negative control of transcription factors, such as cAMP-response element (CRE)-binding protein (CREB). We assessed the effect of calcineurin inhibitors on CREB activation by neuronal activity and show that calcineurin activity is in fact required for CREB-mediated gene expression. However, inhibition of calcineurin had disparate effects on the transcriptional induction of CREB-dependent lEGs. We find that the lEG c-fos is unaffected by suppression of calcineurin activity, the plasticity-related genes Egr1/Zif268 and Egr2/Krox-20 are up-regulated, and genes encoding the orphan nuclear hormone receptors Nor1 and Nur77 are down- regulated. We further show that the up-regulation of particular lEGs is probably due to the presence of serum response elements (SREs) in their promoters, because SRE-mediated gene expression is enhanced by calcineurin blockers. Moreover, expression of the c-fos gene, which is unaffected by calcineurin inhibitors, could be down-regulated by mutating the SRE. Conversely, SRE- mediated c-fos induction in the absence of a functional CRE was enhanced by calcineurin inhibitors. Our experiments thus implicate calcineurin as a negative regulator of SRE-dependent neuronal genes. [ABSTRACT FROM AUTHOR]

Abstract: The myocyte enhancer factor-2 (MEF2) family of Ca2+-regulated transcription factors regulate neuronal development by controlling synapse formation and supporting the survival of newly formed neurons. MEF2 proteins could potentially also influence early aspects of neuronal differentiation such as neuronal fate specification and their subsequent morphological and functional maturation. We used immunocytochemistry to examine the expression of the isoform MEF2D during the differentiation of embryonic rat neural progenitor cells as a step towards evaluating the role of MEF2 factors in early events of neuronal differentiation. We show here that MEF2D is expressed in both proliferating neural precursor cells and in differentiated cells that acquire neuronal or glial phenotypes. However, in cells that adopt a neuronal phenotype, MEF2D expression in the nucleus increases progressively during the course of differentiation while decreasing in glial cells. Furthermore, in newly formed neurons the level of MEF2D expression correlates positively with the length of neurite projections. [Copyright &y& Elsevier]