Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor.
Hepatocyte growth factor (HGF) has been shown to function as a potent mitogen for a variety of cells, transducing its signal through the c-met tyrosine kinase receptor. Ciliary neurotrophic factor (CNTF) is a cytokine that has been shown to promote survival of motor neurons. We show here that c-met mRNA is present in the embryonic rat spinal cord. Peak expression of c-met (at E14) coincides with the period of naturally occurring cell death in motor neurons, suggesting a possible role of HGF in the regulation of this process. Utilizing a neuron-enriched culture system, we established that HGF, like CNTF, stimulates choline acetyltransferase (CAT) activity in motor neurons. When co-administered to motor neuron cultures, saturating concentrations of HGF and CNTF produced a synergistic increase in CAT levels. We show that this synergy reflects enhanced motor neuron survival. Exposure of motor neuron cultures to the cytostatic agent vincristine markedly decreased CAT levels; co-treatment with HGF and CNTF (but not either factor alone) restored CAT activity to control levels. Our findings indicate that HGF is a survival factor for motor neurons, that it acts synergistically with CNTF, and that HGF and CNTF can together be neuroprotective in the face of vincristine toxicity.
Wong
V
V
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
Glass
D J
DJ
Arriaga
R
R
Yancopoulos
G D
GD
Lindsay
R M
RM
Conn
G
G
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor; D004357:Drug Synergism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
D020934:Ciliary Neurotrophic Factor; D009419:Nerve Tissue Proteins; D017228:Hepatocyte Growth Factor