NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis.
NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis.
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DOI：
10.1083/jcb.136.2.375
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发表时间：
1997-01-27
期刊：
影响因子：
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通讯作者：
Miller FD
中科院分区：
文献类型：
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作者：
Belliveau DJ;Krivko I;Kohn J;Lachance C;Pozniak C;Rusakov D;Kaplan D;Miller FD
在这份报告中，我们研究了NGF和神经营养因子-3(NT-3)控制交感神经元分化和存活的生物学和分子基础。在NGF依赖的交感神经元中，NT-3和NGF一样有效地介导神经发生和生长相关基因的表达，但在支持它们存活方面的效率要低20-40倍。NT-3和NGF都能诱导类似的持续、长期的TrkA激活，而NGF在调节急性短期TrkA活性方面的效率是NT-3的10倍。在类似的急性TrkA激活水平下，NT-3对神经元存活的调节作用仍然比NGF低两到三倍。然而，激活TrkC而不激活TrkA的突变体NT-3不能支持交感神经元的存活或神经发生，这表明NT3介导的TrkA激活对于这两种反应都是必要的。在这些数据的基础上，我们认为NGF和NT-3在激活时间和下游靶点方面都对TrkA受体进行了不同的调节，从而导致了对神经发生和存活的选择性调节。对通过同一Trk受体作用的两种配体的这种不同反应对整个神经系统的神经营养因子功能具有重要意义。
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 20–40fold 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 NT3–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.