Belliveau D J, Krivko I, Kohn J, Lachance C, Pozniak C, Rusakov D, Kaplan D, Miller F D
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Canada.
J Cell Biol. 1997 Jan 27;136(2):375-88. doi: 10.1083/jcb.136.2.375.
In this report we examine the biological and molecular basis of the control of sympathetic neuron differentiation and survival by NGF and neurotrophin-3 (NT-3). NT-3 is as efficient as NGF in mediating neuritogenesis and expression of growth-associated genes in NGF-dependent sympathetic neurons, but it is 20-40-fold less efficient in supporting their survival. Both NT-3 and NGF induce similar sustained, long-term activation of TrkA, while NGF is 10-fold more efficient than NT-3 in mediating acute, short-term TrkA activity. At similar acute levels of TrkA activation, NT-3 still mediates neuronal survival two- to threefold less well than NGF. However, a mutant NT-3 that activates TrkC, but not TrkA, is unable to support sympathetic neuron survival or neuritogenesis, indicating that NT-3-mediated TrkA activation is necessary for both of these responses. On the basis of these data, we suggest that NGF and NT-3 differentially regulate the TrkA receptor both with regard to activation time course and downstream targets, leading to selective regulation of neuritogenesis and survival. Such differential responsiveness to two ligands acting through the same Trk receptor has important implications for neurotrophin function throughout the nervous system.
在本报告中，我们研究了神经生长因子（NGF）和神经营养因子-3（NT-3）对交感神经元分化和存活进行调控的生物学及分子基础。在介导神经突起生长以及在依赖NGF的交感神经元中诱导生长相关基因表达方面，NT-3与NGF的效率相当，但在支持这些神经元存活方面，其效率要低20至40倍。NT-3和NGF均可诱导TrkA产生相似的持续性、长期激活，而在介导急性、短期的TrkA活性方面，NGF的效率比NT-3高10倍。在相似急性水平的TrkA激活状态下，NT-3在介导神经元存活方面的效果仍比NGF低两至三倍。然而，一种能激活TrkC但不能激活TrkA的突变型NT-3无法支持交感神经元的存活或神经突起生长，这表明NT-3介导的TrkA激活对于这两种反应均是必需的。基于这些数据，我们认为NGF和NT-3在激活时间进程及下游靶点方面对TrkA受体进行了差异调节，从而导致对神经突起生长和存活的选择性调控。对通过同一Trk受体起作用的两种配体的这种差异反应性，对整个神经系统中神经营养因子的功能具有重要意义。
