Semaphorin 3A Stimulates Neurite Extension and Regulates Gene Expression in PC12 Cells

The secreted semaphorin 3A (Sema3A) is a member of a large family of proteins that act as guidance signals for axons and dendrites. While the receptors and signaling pathways that mediate the repulsive effects of semaphorins are beginning to be understood in some detail, the mechanisms that are responsible for the ability of Sema3A to stimulate the extension of dendrites remain to be elucidated. Here we show that PC12 cells, a model widely used to study neuronal differentiation, can be used to dissect this pathway. Sema3A is as effective as nerve growth factor in stimulating the extension of neurites from PC12 cells. We show that Sema3A is able to regulate gene expression and identify mitochondria as a novel target of Sema3A signaling. Pharmacological block of mitochondrial reactive oxygen species production abolishes the extension of neurites in response to Sema3A. These results show that the characterization of transcripts that are regulated by axon guidance signals may help to identify novel components of their signaling pathways.