GDNF as a therapeutic regend for human muscle diseases

已有多种神经营养因子被用于促进运动神经元的存活。胶质细胞源性神经营养因子作为一种靶源性营养因子，通过其受体复合体α-1和c-Ret对运动神经元发挥作用。C-Ret受体酪氨酸激酶是GDNF配体家族的重要组成部分，该家族包括胶质细胞源性神经营养因子、神经突触蛋白、Persephin和青蒿素。虽然c-Ret本身不能与胶质细胞源性神经营养因子结合，但它通过与GFRα-1(胶质细胞源性神经营养因子受体α-1)的复合体传递信号。GFR-1是一种糖基磷脂酰肌醇锚定蛋白，与胶质细胞源性神经营养因子具有高亲和力。因此，配体结合和跨膜信号分别被认为是GFRα-1和c-Ret所特有的。面神经切断诱导成年大鼠面神经胶质细胞生长因子α-1和c-Ret基因表达上调。轴突切断处局部应用胶质细胞源性神经营养因子可上调GFRα-1mRNA的表达，但不能上调c-Ret的表达。提示肾小管上皮细胞生长因子受体α-1和c-Ret上调的机制可能不同。

A variety of neurotrophic factors have been characterized for promoting motor neuron survival. As one of the target-derived trophic factors, glial cell line-derived neurotrophic factor (GDNF) has been shown to exert its effects on motor neurons via a receptor complex including GDNF receptor alpha 1 (GFRα-1) and c-Ret. The c-Ret receptor tyrosine kinase is an essential component of the GDNF ligand family that consists of glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin. Although c-Ret cannot bind GDNF by itself, it transduces signaling in a complex with GFRα-1 (GDNF receptor alpha-1), a glycosyl phosphatidylinositol (GPI)-anchored protein that binds GDNF with high affinity. Thus, the ligand binding and transmembrane signaling are regarded to be specified for GFRα-1 and c-Ret, respectively. Axotomy of facial nerve induced up-regulation of GFRα-1 and c-Ret mRNAs in adult rats. The local administration of GDNF at the site of axotomy resotred up-regulation of GFRα-1 mRNA but not c-Ret. This result indicates that the mechanism of GDNF receptor up-regulation may differ between GFRα-1 and c-Ret.