Hepatocyte Growth Factor Promotes Motor Neuron Survival and Synergizes with Ciliary Neurotrophic Factor

doi:10.1074/jbc.272.8.5187

Hepatocyte Growth Factor Promotes Motor Neuron Survival and Synergizes with Ciliary Neurotrophic Factor*

From Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591

^‡ To whom correspondence should be addressed:
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd., Tarrytown, NY 10591.
Tel.: 914-345-7563; Fax: 914-347-5045.

Abstract

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.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

HGF

hepatocyte growth factor

CNTF

ciliary neurotrophic factor

CAT

choline acetyltransferase

NGF

nerve growth factor

ANOVA

analysis of variance

BDNF

brain-derived neurotrophic factor.
- Received November 14, 1996.