Zhang Jiasheng, Huang Eric J
Department of Pathology, University of California San Francisco and Pathology, Service 113B, VA Medical Center, 94121, USA.
J Neurobiol. 2006 Jul;66(8):882-95. doi: 10.1002/neu.20269.
Neurotrophic factors support the survival of spinal motoneurons (MNs) and have been considered as strong candidates for treating motoneuron diseases. However, it is unclear if the right combination of neurotrophic factor receptors is present in postnatal spinal MNs. In this study, we show that the level of c-ret expression remains relatively stable in embryonic and postnatal spinal MNs. In contrast, the mRNA and protein of GFRalpha1 and -2 are progressively down-regulated in postnatal life. By 3 and 6 months of age, both receptors are barely detectable in spinal MNs. The down-regulation of GFRalpha1 appears accelerated in transgenic mice expressing mutant SOD1(G93A). Despite the progressive loss of GFRalpha1 and -2, phosphorylation of c-ret shows no detectable reduction on tyrosine residues or on serine 696. In addition to the GFRalpha subunits, expression of TrkB also shows a dynamic change. During embryogenesis, there is twice as much full-length TrkB as the truncated TrkB isoform. However, this ratio is reversed in postnatal spinal cord. Expression of the mutant SOD1(G93A) appears to have no effect on the TrkB receptor ratio. Taken together, our data indicate that the expression of neurotrophic factor receptors, GFRalpha1, -2, and TrkB, is not static, but undergoes dynamic changes in postnatal spinal MNs. These results provide insights into the use of neurotrophic factors as therapeutic agents for ALS.
神经营养因子支持脊髓运动神经元（MNs）的存活，并被视为治疗运动神经元疾病的有力候选物。然而，尚不清楚出生后脊髓MNs中是否存在神经营养因子受体的正确组合。在本研究中，我们发现c-ret在胚胎期和出生后脊髓MNs中的表达水平相对稳定。相比之下，GFRalpha1和-2的mRNA及蛋白在出生后逐渐下调。到3个月和6个月大时，脊髓MNs中几乎检测不到这两种受体。在表达突变型SOD1(G93A)的转基因小鼠中，GFRalpha1的下调似乎加速。尽管GFRalpha1和-2逐渐丧失，但c-ret的磷酸化在酪氨酸残基或丝氨酸696上未显示出可检测到的减少。除了GFRalpha亚基外，TrkB的表达也呈现动态变化。在胚胎发育过程中，全长TrkB的量是截短型TrkB异构体的两倍。然而，在出生后的脊髓中，这个比例发生了逆转。突变型SOD1(G93A)的表达似乎对TrkB受体比例没有影响。综上所述，我们的数据表明神经营养因子受体GFRalpha1、-2和TrkB的表达并非静止不变，而是在出生后脊髓MNs中经历动态变化。这些结果为将神经营养因子用作肌萎缩侧索硬化症的治疗药物提供了见解。
