During central nervous system development, growth factors and their associated 
receptor protein tyrosine kinases regulate many neuronal functions such as 
neurite extension and dendrite maturation. Hepatocyte growth factor (HGF) and 
its receptor, c-Met, can promote formation of neurites and enhance elaboration 
of dendrites in mature neurons, but their effects on the early stages of 
dendrite maturation in hippocampal neurons and the signaling pathways by which 
they promote dendrite formation have not been studied. Exogenous HGF treatment 
effectively enhanced the phosphorylation and activation of c-Met in cultured 
hippocampal neurons at 4 days in vitro. HGF treatment increased the number of 
dendrites and promoted dendrite elongation in these neurons. Consistent with 
these results, HGF activated Akt, which phosphorylates glycogen synthase 
kinase-3beta (GSK-3beta) to inactivate it, and reduced phosphorylation of 
microtubule-associated protein 2 (MAP2), which can promote microtubule 
polymerization and dendrite elongation when dephosphorylated. Conversely, 
pharmacological inhibition of c-Met with its specific inhibitor, PHA-665752, or 
genetic knock-down of c-Met with short hairpin RNAs (shRNAs) suppressed 
HGF-induced phosphorylation of Akt and GSK-3beta, increased phosphorylation of 
MAP2, and reduced dendrite number and length in cultured hippocampal neurons. 
Moreover, suppressing c-Met with PHA-665752 or by shRNA decreased MAP2 
expression. Inhibiting Akt activity with the phosphoinositide-3-kinase inhibitor 
LY294002 or Akt inhibitor X suppressed HGF-induced phosphorylation of GSK-3beta, 
increased MAP2 phosphorylation, and blocked the ability of HGF to enhance 
dendritic length. These observations indicate that HGF and c-Met can regulate 
the early stages of dendrite maturation via activation of the Akt/GSK-3beta 
pathway.