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The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway
Author(s) -
Jones David M.,
Tucker Budd A.,
Rahimtula Masuma,
Mearow Karen M.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01925.x
Subject(s) - neurite , nerve growth factor , mapk/erk pathway , protein kinase b , neurotrophin , tropomyosin receptor kinase a , microbiology and biotechnology , growth factor , biology , signal transduction , dorsal root ganglion , chemistry , medicine , endocrinology , neuroscience , sensory system , biochemistry , receptor , in vitro
Nerve growth factor (NGF) and insulin‐like growth factor‐1 (IGF‐1) play an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Adult DRG neurons exhibit neurotrophin‐independent survival, providing an excellent system with which to study trophic factor effects on neurite growth in the absence of significant survival effects. Using young adult rat DRG neurons we have demonstrated a synergistic effect of NGF plus IGF (N + I), compared with either factor alone, in promoting neurite growth. Not only does the presence of NGF and IGF‐1 enhance neurite initiation, it also significantly augments the extent of neurite branching and elongation. We have also examined potential mechanism(s) underlying this synergistic effect. Immunoblotting experiments of classical growth factor intermediary signalling pathways (PI 3‐K‐Akt‐GSK‐3 and Ras‐Raf‐MAPK) were performed using phospho‐specific antibodies to assess activation state. We found that activation of Akt and MAPK correlated with neurite elongation and branching. However, using pharmacological inhibitors, we observed that a PI 3‐K pathway involving both Akt and GSK‐3 appeared to be more important for neurite extension and branching than MAPK‐dependent signalling. In fact, inhibition of activation of MAPK with U0126 resulted in increased neuritic branching, possibly as a result of the concomitant increase observed in phospho‐Akt. Furthermore, inhibition of GSK3 (which is negatively regulated by phosphorylation on S9/S21) also resulted in increased growth. Our data point to signalling convergence upon the PI 3‐K‐Akt‐GSK‐3 pathway that underlies the NGF plus IGF synergism. In addition, to our knowledge, this is the first report in primary neurons that inhibition of GSK3 results in an enhanced neurite growth.