A decline in developing neuronal cAMP levels appears to render mammalian axons susceptible to growth inhibitory factors in the damaged CNS. cAMP elevation enhances axon regeneration, but the cellular mechanisms involved have yet to be fully elucidated. Epac has been identified as a signaling protein that can be activated by cAMP independently of PKA, but little is known of its expression or role in the nervous system. We report that Epac expression is developmentally regulated in the rat nervous system, and that activation of Epac promotes DRG neurite outgrowth and is as effective as cAMP elevation in promoting neurite regeneration on spinal cord tissue. Additionally, siRNA mediated knockdown of Epac reduces DRG neurite outgrowth, prevents the increased growth promoted by cAMP elevation and also diminishes the ability of embryonic neurons to grow processes on spinal cord tissue. Furthermore, we show that asymmetric activation of Epac promotes attractive growth cone turning in a similar manner to cAMP activation. We propose that Epac plays a role in mediating cAMP-dependent axon growth and guidance, and may provide an important target for inducing axon regeneration in vivo. (C) 2008 Elsevier Inc. All rights reserved.