Differential regulation of axonal growth and neuromuscular junction assembly by HGF/c-Met signaling.
BACKGROUND
During vertebrate neuromuscular junction (NMJ) development, contact between motor axons and muscle fibers is followed by pre- and post-synaptic specialization. Using Xenopus nerve-muscle cocultures, we recently showed that spinal neurons initially contacted muscle cells by means of filopodial processes, and that muscle-derived basic fibroblast growth factor induced axonal filopodia and slowed axonal advance to promote nerve-muscle interaction and NMJ establishment. In contrast, neurotrophins enhanced axonal growth but suppressed the extension of axonal filopodia and blocked NMJ formation.


RESULTS
Here we report that hepatocyte growth factor (HGF), which also supports motor neuron survival, was expressed by Xenopus muscle cells, and that forced expression of HGF in Xenopus spinal neurons inhibited the extension of axonal filopodia. Overexpression of the HGF-receptor c-Met in neurons also blocked the formation of axonal filopodia and furthermore sped up axonal growth, but a kinase-dead form of c-Met was unable to effect these changes. Importantly, treatment of nerve-muscle cocultures with recombinant HGF or the expression of HGF or active c-Met in neurons, or that of excess HGF in muscle, inhibited nerve-induced AChR clustering in muscle.


CONCLUSIONS
Our results suggest that HGF/c-Met signaling in neurons promotes axonal growth but suppresses filopodial assembly in neurons and hinders NMJ establishment.
Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
Pan P
PP
Li
Raghavan
R
Madhavan
H Benjamin
HB
Peng
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D018929:Cell Culture Techniques; D017931:DNA Primers / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008853:Microscopy; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D014981:Xenopus
D017931:DNA Primers; D009414:Nerve Growth Factors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met