Functional analysis of HGF and its family member (HLP): from the basic to the potential application to neural diseases

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Hepatocyte growth factor (HGF) was first purified as a mitogen for primary hepatocyte, and molecularly cloned in 1989. In 1995, our group identified HGF as a neurotrophic factor using primary hippocampal neurons. We here focused on the elucidation of the role of HGF both during neural development and in one of the neurodegenerative diseases, amyotrophic lateral sclerosis (ALS). During cortical development, HGF and c-Met/HGF receptor was regionally and sequentially regulated in a concerted fashion.In addition, HGF promoted neural migration and survival of cortical neurons, analyzed in primary dissociated neuroual culture and slice culture of cerebral cortex. These suggested the implication of HGF in cortical layer formation. To assess the role of HGF in ALS, we first generated trausgenic mice overexposing HGF in a neuron specific manner (HGF-Tg).HGF-Tg was mated with transgenic mice overrexpressing mutant SOD1 (ALS-Tg), transgenic mice model of ALS. Transgenic mice overexposing both HGF … More and mutant SOD1 (HGF/ALS-Tg). showed the attenuation of motoneuronal death, delayed onset, improved motor function and prolonged life span of ALS mice. Histological, western blotting, quantitative competitive RT-PCR analyzes together with primary culture study of neural cells revealed that HGF improves, ALS by attenuating induction of caspase-1 in motoneurons and by preventing reduction of gluamate transporter in astrocytes. These suggest the potential therapeutic activities of HGF on ALS and related disorders.HGF-like protein (HLP/MSP) is a family member of HGF HGF and its receptor Ron were expressed in the nervous system. However, function of HLP in the nervous system is not well understood. We found that HLP acts as a neurotrophic factor using chick dorsal ganglion explants. A chimeric receptor composed of extracellular and trausmembrane domains of Ron fused with immunoglobuline (Rou-Fc) eliminated activities of HLP on chick sensory ganglia, such as migration and neurite outgrowth promoting activities. This is the first evidence that HLP acts as a neurotrophic factor. Less