Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T
Division of Biochemistry, Osaka University Medical School, Japan.
Brain Res Mol Brain Res. 1995 Sep;32(2):197-210. doi: 10.1016/0169-328x(95)00075-4.
Hepatocyte growth factor (HGF), a natural ligand for the c-met protooncogene product, has mitogenic, motogenic and morphogenic activities for various cell types and functions as a organotrophic factor for regeneration of the liver, kidney and lung. We obtained evidence that HGF may function as a novel neurotrophic factor in the central nervous system. Northern blot analysis showed that 6 kb HGF mRNA and 9 kb c-Met/HGF receptor mRNA are expressed in various regions of the adult rat brain. In situ hybridization analysis revealed that intense hybridization signals for HGF mRNA were localized in cerebral cortex, hippocampus and amygdala. Consistently, specific localization of HGF protein in neurons of these regions was detected by immunohistochemical analysis and non-neuronal glial cells in cingulum, cerebellum, pons and medulla were also specifically stained. Specific intense hybridization signals for c-Met/HGF receptor mRNA were also widely distributed in the brain, including neurons of olfactory bulb, cerebral cortex, primary olfactory cortex, hippocampus and cerebellum. On the basis of the co-expression of HGF and c-Met/HGF receptor in hippocampal neurons, we found that HGF prolonged survival of embryonic hippocampal neurons in primary culture: HGF elicited maximal surviving effect at 0.5-1 ng/ml and the potency was comparable to that of nerve growth factor. More importantly, expression of both HGF and c-Met/HGF receptor mRNAs was markedly induced in response to cerebral ischemic injury. We propose that HGF functions as a neurotrophic factor in the central nervous system and that this neurotrophic function may have a role in the survival and reconstruction of specific neurons in response to cerebral injury.
肝细胞生长因子（HGF）是原癌基因c-met产物的天然配体，对多种细胞类型具有促有丝分裂、促运动和促形态发生活性，并作为肝脏、肾脏和肺再生的器官营养因子发挥作用。我们获得的证据表明，HGF可能在中枢神经系统中作为一种新型神经营养因子发挥作用。Northern印迹分析显示，6 kb的HGF mRNA和9 kb的c-Met/HGF受体mRNA在成年大鼠脑的各个区域表达。原位杂交分析表明，HGF mRNA的强烈杂交信号定位于大脑皮层、海马体和杏仁核。一致地，通过免疫组织化学分析检测到HGF蛋白在这些区域的神经元中特异性定位，并且扣带、小脑、脑桥和延髓中的非神经元神经胶质细胞也被特异性染色。c-Met/HGF受体mRNA的特异性强烈杂交信号也广泛分布于大脑中，包括嗅球、大脑皮层、初级嗅觉皮层、海马体和小脑的神经元。基于海马神经元中HGF和c-Met/HGF受体的共表达，我们发现HGF延长了原代培养的胚胎海马神经元的存活时间：HGF在0.5-1 ng/ml时产生最大存活效应，其效力与神经生长因子相当。更重要的是，HGF和c-Met/HGF受体mRNA的表达在脑缺血损伤后均明显诱导。我们提出，HGF在中枢神经系统中作为神经营养因子发挥作用，并且这种神经营养功能可能在脑损伤后特定神经元的存活和重建中起作用。
