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

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.

The Novel GTPase Rit Differentially Regulates Axonal and Dendritic Growth

“…In agreement with this, we found that Rit activates ERK1/2 in neurons and pharmacological inhibition of MEK1 blocks both the axon-promoting and dendrite-inhibiting activity of caRit. These data are consistent with reports that MEK/ERK signaling enhances axonal growth in sympathetic (Atwal et al, 2000;Thompson et al, 2004) and hippocampal (Gerecke et al, 2004) neurons and with our previous observations that BMP7-induced dendritic growth in sympathetic neurons is potentiated by inhibition of MEK/ERK activation (Kim et al, 2004). However, our findings contrast with reports that MEK/ERK signaling mediates activitydependent increases in dendritic growth in both hippocampal (Wayman et al, 2006) and sympathetic neurons (Vaillant et al, 2002), suggesting that MEK/ ERK activation alone is not sufficient to fully explain Rit effects on axonal and dendritic growth.…”

“…Although the molecular mechanisms underlying the paradoxical effects of combined NGF and BMP signaling on Rit activation are not known at this time, the observation is consistent with previous reports that in sympathetic neurons, ERK1/2 signaling negatively impacts BMP7-induced dendritic growth (Kim et al, 2004) and that BMP7-induced dendritic growth requires NGF (Lein et al, 1995). Moreover, it has interesting implications regarding the role of NGF signaling in dendritic growth in sympathetic neurons.…”

ERK signaling is required for eye-specific retino-geniculate segregation

“…Indeed, it is noted that the level of ERK activity is a crucial component during plastic processes. For example, it has been reported that either blockade or overexpression of ERK signaling reduces LTP levels or enhances dendritic growth (English and Sweatt, 1997;Kim et al, 2004;Komiyama et al, 2002). Considering these observations, we may suppose that, during the formation of a correct retinothalamic pattern ERK signaling may be induced not only by electrical activity but also by neurotrophins, which together act in concert to finely regulate the eye-specific segregation.…”

“…Mazzucchelli et al, 2002). Recent findings have highlighted the importance of ERKs in visual cortical plasticity (Di Cristo et al, 2001), and in morphological changes in dendritic or axonal structure (Kim et al, 2004;Markus et al, 2002;Vaillant et al, 2002;Wu et al, 2001).…”

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism

“…Cultured PFC neurons [11 d in vitro (DIV)] were cotransfected with a plasmid encoding the enhanced green fluorescent protein (EGFP) (Clontech, Cambridge, UK) and a plasmid containing either the wild-type MEK1 [wtMEK1 (mitogen-activated protein kinase kinase 1)] or the dominant-negative MEK1 (dnMEK1) (carrying M substitution at K97) construct (Kim et al, 2004). In some experiments, NR2B tagged with GFP at the extracellular N terminus (Luo et al, 2002) was used to transfect cultured PFC neurons.…”