Mitogen‐activated protein kinase inhibition reveals differences in signalling pathways activated by neurotrophin‐3 and other growth‐stimulating conditions of adult mouse dorsal root ganglia neurons

Abstract

PD98059 blocks mitogen-activated protein kinase (MAPK) by inhibiting its activator, MAP kinase kinase (MEK). We have previously found that PD98059 only transiently inhibits spontaneous axonal outgrowth from adult mouse dorsal root ganglia (DRG) explants, whereas it causes sustained inhibition of nerve growth factor (NGF)-stimulated growth. Surprisingly, the present results showed that outgrowth stimulation by neurotrophin-3 (NT-3), interacting with another neuronal subgroup, was markedly enhanced by PD98059 and also by U0126, another inhibitor of MAPK activation. In contrast, the effects of glial cell line-derived neurotrophic factor (GDNF), which stimulates still another subgroup of DRG neurons, was opposed by PD98059. Axonal outgrowth in vitro can also be strongly increased by a prior axotomy in vivo. The increased outgrowth in preaxotomized explants was effectively inhibited by the presence of PD98059. Immunocytochemistry based on whole-mount labelling revealed the presence of neuronal MAPK, which was found to be activated by NGF, NT-3, and GDNF in separate axonal populations and by a prior axotomy in a majority of growing axons. The results suggest that there are important differences in the NGF and NT-3 signalling pathways, which may involve positive and negative control mechanisms by MAPK activation, respectively. Other findings indicate that GDNF exerts its growth effects by activation of MAPK and that expression of the conditioning effect in vitro in preaxotomized preparations also requires activation of MAPK.

Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat

“…These key networks cover the most important pathways that play important roles in regulating this differential gene expression through mainly biological GO processes during WD after sciatic nerve injury. The data shown here are consistent with published reports [15][16][17] and supported the conclusion that developing and regenerating peripheral nerves exhibit differences in genetic programs. Further, the data revealed that signal transducers were significantly regulated in the lesioned distal stump after sciatic nerve injury.…”

“…Many genes and related proteins are differentially expressed during WD, the latter including cytokines, neurotrophic factors, axonal myelin and cell adhesion molecules [11][12][13][14][15][16][17][18] . The development of tissue biochemistry and molecular biology, together with improvements in microscopic resolution, has largely facilitated the understanding of the significance of WD in the processes of nerve degeneration and subsequent repair/regeneration [11][12][13][14][15][16][17][18] . Understanding the molecular mechanisms of axonal debris and myelin clearance after processed using GeneSpring GCOS1.2 software.…”

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

“…The ERK signaling pathway regulates crucial aspects of neuronal development, including cellular survival and differentiation (Traverse et al, 1992;Pang et al, 1995;Bergmann et al, 1998;Kurada and White, 1998;Anderson and Tolkovsky, 1999;Atwal et al, 2000;Wiklund et al, 2002). Activation of the ERK signaling pathway has also been found to alter axonal growth in sympathetic, sensory, and spinal motor neurons (Atwal et al, 2000; 2 ) than in previous experiments.…”

“…Inhibition of MEK activation inhibits neuritic growth in PC12 cells (Cowley et al, 1994;Pang et al, 1995) and axonal regeneration after axotomy in sensory neurons of the dorsal root ganglia (Sjogreen et al, 2000;Wiklund et al, 2002). Therefore, we used two methods to determine whether PD 98059 affects axonal growth in our system (Fig.…”

“…Of particular interest is the ERK pathway, which has many effects on neural tissues. For example, activation of ERKs increases axonal growth in sympathetic neurons (Atwal et al, 2000), dorsal root ganglia (Sjogreen et al, 2000;Wiklund et al, 2002), and PC12 cells (Traverse et al, 1992;Pang et al, 1995) in vitro, and it also enhances axonal regeneration after axotomy in vivo (Miura et al, 2000). In addition, ERK stimulation plays an important role in activity-dependent regulation of neuronal functions, such as synaptic plasticity, learning, and memory (Grewal et al, 1999;Adams and Sweatt, 2002).…”