HuD is a neuronal-specific RNA-binding protein that binds to and stabilizes the mRNAs of growth-associated protein-43 (GAP-43) and other neuronal proteins. HuD expression increases during brain development, nerve regeneration, and learning and memory, suggesting that this protein is important for controlling gene expression during developmental and adult plasticity. To examine the function of HuD in vivo, we generated transgenic mice overexpressing human HuD under the control of the calcium-calmodulin-dependent protein kinase IIalpha promoter. The transgene was expressed at high levels throughout the forebrain, including the hippocampal formation, amygdala and cerebral cortex. Using quantitative in situ hybridization, we found that HuD overexpression led to selective increases in GAP-43 mRNA in hippocampal dentate granule cells and neurons in the lateral amygdala and layer V of the neorcortex. In contrast, GAP-43 pre-mRNA levels were unchanged or decreased in the same neuronal populations. Comparison of the levels of mature GAP-43 mRNA and pre-mRNA in the same neurons of transgenic mice suggested that HuD increased the stability of the transcript. Confirming this, mRNA decay assays revealed that the GAP-43 mRNA was more stable in brain extracts from HuD transgenic mice than non-transgenic littermates. In conclusion, our results demonstrate that HuD overexpression is sufficient to increase GAP-43 mRNA stability in vivo.