Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins

Abstract

The view that memory is encoded by variations in the strength of synapses implies that long-term biochemical changes take place within subcellular microdomains of neurons. These changes are thought ultimately to be an effect of transcriptional regulation of specific genes. Localized changes, however, cannot be fully explained by a purely transcriptional control of gene expression. The neuron-specific ELAV-like HuB, HuC, and HuD RNA-binding proteins act posttranscriptionally by binding to adenine-and uridinerich elements (AREs) in the 3 untranslated region of a set of target mRNAs, and by increasing mRNA cytoplasmic stability and͞or rate of translation. Here we show that neuronal ELAV-like genes undergo a sustained up-regulation in hippocampal pyramidal cells only of mice and rats that have learned a spatial discrimination paradigm. This learning-specific increase of ELAV-like proteins was localized within cytoplasmic compartments of the somata and proximal dendrites and was associated with the cytoskeleton. This increase was also accompanied by enhanced expression of the GAP-43 gene, known to be regulated mainly posttranscriptionally and whose mRNA is demonstrated here to be an in vivo ELAV-like target. Antisense-mediated knockdown of HuC impaired spatial learning performance in mice and induced a concomitant downregulation of GAP-43 expression. Neuronal ELAV-like proteins could exert learning-induced posttranscriptional control of an array of target genes uniquely suited to subserve substrates of memory storage.

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

“…For example, mRNA stabilization by ELAV-like proteins is required for learning and memory formation (Quattrone et al, 2001) and upregulation of bcl-2 expression is seen as highly significant in the treatment or prevention of a number of neurodegenerative disorders (Deigner et al, 2000).…”

Behavioral deficits associated with fetal alcohol exposure are reversed by prenatal thyroid hormone treatment: a role for maternal thyroid hormone deficiency in FAE

“…Overexpression of GAP-43, a substrate of protein kinase C, has been found to enhance learning, 32 while downregulation of GAP-43 expression impairs learning. 34,61 The importance of decreased hippocampal expression of GAP-43 is emphasized by recent studies showing decreased phosphorylated GAP-43 in the hippocampus of adult FAE rats 62 and in adult FAE male offspring in response to contextual fear conditioning. 63 These results corroborate the potential significance of hippocampal GAP-43 in learning/memory impairment of FAE offspring, as animals expressing the constitutively phosphorylated form of GAP-43 exhibit increased learning.…”

“…31 The goals of the present study were to determine the effects of FAE and prenatal T4 administration on the adult offspring's spatial learning and memory and depressive behavior, and on the expression of genes known to be associated with these behaviors in specific brain regions. The selected genes, GAP-43 [32][33][34] and glucocorticoid receptor (GR), 35 have been extensively studied and implicated in learning, and GR has also been suggested to influence behavior in the FST. [36][37][38][39] Materials and methods…”

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

“…In vitro analyses have shown that these proteins can bind to AREs (19, 22, 26 -31). Experiments in tissue culture, in vitro decay analyses, and in vivo studies have demonstrated direct effects of Hu proteins on the levels and/or stability of ARE-containing mRNAs (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). Hu proteins have also been implicated in cancer, as they are overexpressed in neuroblastoma and small cell lung cancer, two types of cancer that show stabilization of labile proto-oncogene mRNAs such as those of the MYC, MYCN, and FOS genes (35,46,47).…”