White F A, Silos-Santiago I, Molliver D C, Nishimura M, Phillips H, Barbacid M, Snider W D
Center for the Study of Nervous System Injury, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 1996 Aug 1;16(15):4662-72. doi: 10.1523/JNEUROSCI.16-15-04662.1996.
Determinations of dorsal root ganglion (DRG) neuron loss in nerve growth factor (NGF) and neurotrophin-3 (NT-3) null mutant mice have supported the concept that neurons can switch neurotrophin dependence by revealing that many neurons must require both of these factors acting either sequentially or simultaneously during development. The situation is complex, however, in that NT-3(-/-) mutant mice show far greater neuron loss than mice deficient in the NT-3 receptor TrkC, suggesting that NT-3 may support many DRG neurons via actions on the NGF receptor TrkA. To assess the possibility of ligand-receptor cross-talk as a developmental mechanism, we have compared the onset of survival dependence of lumbar DRG neurons on NT-3, TrkC, NGF, and TrkA signaling in mice deficient in these molecules as a result of gene targeting. At embryonic day 11.5 (E11.5), virtually all lumbar DRG cells express TrkC mRNA and many require NT-3 and TrkC signaling for survival. In contrast, although many lumbar DRG cells also express TrkA at E11.5, there is little survival dependence on TrkA signaling. By E13.5, most lumbar DRG cells have downregulated TrkC mRNA. The onset of survival dependence on NGF and TrkA-signaling is concurrent and of equal magnitude at E13.5, demonstrating that NT-3 alone does not support DRG neurons via TrkA, nor can NT-3 compensate for the loss of NGF. We conclude that many murine DRG cells require NT-3 activation of TrkA is unimportant to these early NT-3 survival-promoting actions. We suggest that the discrepancy in cell loss between NT-3(-/-) and trkC(-/-) mutants is attributable to the ability of NT-3 to support DRG neurons via TrkA in the artificial situation where TrkC is absent.
对神经生长因子（NGF）和神经营养素-3（NT-3）基因敲除突变小鼠背根神经节（DRG）神经元损失的测定支持了这样一种概念，即神经元可以通过揭示许多神经元在发育过程中必须依次或同时需要这两种因子来切换神经营养素依赖性。然而，情况很复杂，因为NT-3基因敲除（-/-）突变小鼠显示出比缺乏NT-3受体TrkC的小鼠更大的神经元损失，这表明NT-3可能通过作用于NGF受体TrkA来支持许多DRG神经元。为了评估配体-受体相互作用作为一种发育机制的可能性，我们比较了由于基因靶向而缺乏这些分子的小鼠中腰段DRG神经元对NT-3、TrkC、NGF和TrkA信号的存活依赖性的起始情况。在胚胎第11.5天（E11.5），几乎所有腰段DRG细胞都表达TrkC mRNA，许多细胞需要NT-3和TrkC信号来存活。相比之下，虽然许多腰段DRG细胞在E11.5时也表达TrkA，但对TrkA信号的存活依赖性很小。到E13.5时，大多数腰段DRG细胞下调了TrkC mRNA。在E13.5时，对NGF和TrkA信号的存活依赖性起始是同时的且程度相同，这表明单独的NT-3不能通过TrkA支持DRG神经元，NT-3也不能补偿NGF的损失。我们得出结论，许多小鼠DRG细胞需要NT-3激活TrkA对这些早期NT-3促进存活的作用并不重要。我们认为NT-3基因敲除（-/-）和TrkC基因敲除（-/-）突变体之间细胞损失的差异可归因于在缺乏TrkC的人工情况下NT-3通过TrkA支持DRG神经元的能力。
