HGF family that includes HGF & HLP/MSP as a novel neurotrophic family

我们以前发现HGF及其家族成员HGF样蛋白（HLP）/MSP是一种新的神经营养因子，对大脑皮层、海马、中脑多巴胺能、感觉、运动和交感神经元等多种神经元均有作用。在本研究中，我们进一步研究了HGF和HLP在神经系统，特别是在神经退行性疾病中的作用。另外，通过对LIMK-2基因敲除小鼠的制备和分析，我们发现LIMK-2激酶2在神经元退行性变过程中起重要作用。(1)HGF在肌萎缩侧索硬化症（ALS）中的作用：肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征在于运动神经元的进行性丧失和运动轴突的变性。我们发现，肝细胞生长因子（HGF）在神经系统中的过度表达减弱了运动神经元死亡和轴突变性，并延长了过度表达突变SOD 1的转基因小鼠的寿命。HGF阻止运动神经元中caspase-1的诱导， 关于我们 d保留了反应性星形胶质细胞中胶质细胞特异性谷氨酸转运体（EAAT 2/GLT 1）的水平。我们建议，肝细胞生长因子可能是第一个例子的内源性生长因子，可以减轻ALS的症状，通过对运动神经元的直接神经营养活动和对神经胶质细胞的间接活动，大概有利于减少神经元的神经毒性。(2)HLP/MSP在神经系统中的作用：我们以前报道过HLP作为一种新的鸡感觉神经元的神经营养因子。在这里，我们确定了罗恩/HLP受体在原代小胶质细胞中表达，并且HLP在体外加速小胶质细胞的活动。结合HLP具有神经营养性的观点，HLP可能是参与神经退行性变的保护过程以及神经系统退行性变和再生过程的关键因素之一。(3)LIMKase-2（LIMK 2）在神经系统中的作用：通过建立LIMK 2缺陷小鼠模型并分析，发现LIMK 2变异体在海马神经元中表达差异，并在海马神经元变性过程中发挥重要作用。少

We previously indeitified that HGF and its family member, HGF-like protein (HLP)/MSP are novel neurotrophic factors for variety of neurons, such as cerebral cortex, hippocampus, midbrain dopaminergic, sensory, motor and sympathetic neurons. In the current study, we further investigated the roles of HGF and HLP in the nervous system, especially in neurodegenerative diseases. In addition, by generation and analyses of LIMK-2 KO mice, we found that LIM-kinase 2 play an important role in neuronal degenerative process.(1) Roles of HGF in amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We showed that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated SOD1. HGF prevented induction of caspase-1 in motoneurons an … More d retained the levels of the glial-specific glutamate transporter (EAAT2/GLT1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.(2) Roles of HLP/MSP in the nervous system: We previously reported that HLP act as a novel neurotrophic factor for chicken sensory neurons. Here we identified that Ron/HLP receptor is expressed in primary microglia and HLP accelerates microglial activities in vitro. Taken together with notion that HLP is neurotrophic, HLP may be one of the critical factor involving not only the protecting process of the neurodegeneration but also the degeneration and regeneration processes of the nervous system.(3) Roles of LIMKase-2 (LIMK2) in the nervous system: By generation and analyses if LIMK2 deficient mice, we found that limk2 variants were differently expressed in hippocampal neurons and play important roles in neurodegenerative process of hippocampal neurons. Less