Background:The role of JIP3 in axon specification and elongation in addition to axon branching remains unknown. Results: JIP3 locally activates the JNK-cofilin pathway at axon tips and thus enhances axon elongation. Conclusion: JIP3 is essential for axon elongation. Significance: These results advance our understanding of the role of JIP3 in axon development.

Brain-derived neurotrophic factor (BDNF) has been implicated in the potent modulation of synaptic plasticity at both presynaptic and post-synaptic sites. However, the molecular mechanism underlying BDNF-mediated pre-synaptic modulation remains incompletely understood. Here, we report that BDNF treatment for over 4 h could significantly enhance the expression of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) in cultured hippocampal neurons. This enhancement could be blocked by the Trk inhibitor K252a or by a cAMP response element-binding protein (CREB) inhibitor. In addition, chromatin immunoprecipitation (ChIP) assays revealed that CREB could bind with the JIP3 promoter region and the BDNF treatment could increase this binding. Using dual-luciferase assays we further characterized the cAMP response element (CRE) site in the JIP3 promoter. Finally, we found that BDNF-increased JIP3 expression contributes to the BDNF-induced modulation of neurotransmitter release. Together, our studies reveal that in hippocampal neurons BDNF up-regulates JIP3 expression via CREB activation, which contributes to the enhancement of neurotransmitter release; thus, we have identified a novel mechanism that BDNF modulates pre-synaptic transmission. Keywords: brain-derived neurotrophic factor, cAMP response element-binding protein, hippocampal neurons, JIP3, neurotransmitter release.