MAPK signal transduction pathway mediates agrin effects on neurite elongation in cultured hippocampal neurons.

We have previously shown that agrin regulates the rates of axonal and dendritic elongation by modulating the expression of microtubule-associated proteins in cultured hippocampal neurons. However, the mechanisms by which agrin-induced signals are propagated to the nucleus where they can lead to the phosphorylation, and hence the activation, of transcription factors, are not known. In the present study, we identified downstream elements that play essential roles in the agrin-signaling pathway in developing central neurons. Our results indicate that agrin induces the combined activation of the extracellular signal-regulated kinases (ERK1/ERK2) and p38 in central neurons. In addition, they showed that PD98059 and SB202190, synthetic inhibitors of ERK1/ERK2 and p38 respectively, prevented the changes in the rate of neurite elongation induced by agrin in cultured hippocampal neurons. Collectively, these results suggest that agrin might modulate the expression of neuron-specific genes involved in neurite elongation by inducing CREB phosphorylation through the activation of the MAPK signal transduction pathway in cultured hippocampal neurons. Copyright 2003 Wiley Periodicals, Inc. J Neurobiol 55: 14-24, 2003