Extracellular Signal-Regulated Kinases Regulate Dendritic Growth in Rat Sympathetic Neurons

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Abstract
NGF activates several signaling cascades in sympathetic neurons. We examined how activation of one of these cascades, the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase pathway, affects dendritic growth in these cells. Dendritic growth was induced by exposure to NGF and BMP-7 (bone morphogenetic protein-7). Exposure to NGF increased phosphorylation of ERK1/2. Unexpectedly, two MEK (MAP kinase kinase) inhibitors (PD 98059 and U 0126) enhanced dendritic growth, and a ligand, basic FGF, that activates the ERK pathway inhibited the growth of these processes. The enhancement of dendritic growth by PD 98059 was associated with an increase in the number of axo-dendritic synapses, and it appeared to represent a specific morphogenic effect because neither axonal growth nor cell survival was affected. In addition, increased dendritic growth was not observed after exposure to inhibitors of other signaling pathways, including the phosphatidylinositol-3-kinase inhibitor LY 294002. Dendritic growth was also increased in cells transfected with dominant-negative mutants of MEK1 and ERK2 but not with dominant-negative mutants of MEK5 and ERK5, suggesting that ERK1/2 is the primary mediator of this effect. Exposure to BMP-7 induces nuclear translocation of Smad1 (Sma- and Mad-related protein 1), and PD 98059 treatment potentiated nuclear accumulation of Smad-1 induced by BMP-7 in sympathetic neurons, suggesting a direct enhancement of BMP signaling in cells treated with an MEK inhibitor. These observations indicate that one of the signaling cascades activated by NGF can act in an antagonistic manner in sympathetic neurons and reduce the dendritic growth induced by other NGF-sensitive pathways.