Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons
Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons
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DOI：
10.1101/gad.11.24.3341
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发表时间：
1997-12-15
影响因子：
10.5
通讯作者：
Klein, R
中科院分区：
文献类型：
--
作者：
Maina, F;Hilton, MC;Klein, R
神经系统的发育是一个动态的过程，在此过程中，各种因素以指导性的方式作用，以指导神经元的分化和存活，并诱导轴突生长、导向和靶组织内的末端分支。在这里，我们报告说，小鼠表达的信号突变体的肝细胞生长因子（HGF）受体，蛋氨酸酪氨酸激酶，显示出显着减少的感觉神经支配的皮肤的四肢和胸部，牵连的HGF/Met系统的感觉神经元的发展。利用体外实验，我们发现HGF与神经生长因子（NGF）合作，以促进培养的背根神经节（DRG）神经元的轴突生长。HGF还在体外增强了NGF的神经营养活性，并且体内一定比例的DRG神经元的存活需要Met受体信号传导。这种协同作用对NGF是特异性的，但对相关的神经营养因子BDNF和NT 3不是。通过使用Met的温和信号突变体，我们先前已经证明Met需要通过衔接分子Grb 2的信号传导来诱导成肌细胞的增殖。相比之下，HGF对感觉神经元的作用是由不同于Grb 2的Met效应子介导的。我们的研究结果表明，在发育过程中，神经元需要Met信号。
The development of the nervous system is a dynamic process during which factors act in an instructive fashion to direct the differentiation and survival of neurons, and to induce axonal outgrowth, guidance to, and terminal branching within the target tissue. Here we report that mice expressing signaling mutants of the hepatocyte growth factor (HGF) receptor, the Met tyrosine kinase, show a striking reduction of sensory nerves innervating the skin of the limbs and thorax, implicating the HGF/Met system in sensory neuron development. Using in vitro assays, we find that HGF cooperates with nerve growth factor (NGF) to enhance axonal outgrowth from cultured dorsal root ganglion (DRG) neurons. HGF also enhances the neurotrophic activities of NGF in vitro, and Met receptor signaling is required for the survival of a proportion of DRG neurons in vivo. This synergism is specific for NGF but not for the related neurotrophins BDNF and NT3. By using a mild signaling mutant of Met, we have demonstrated previously that Met requires signaling via the adapter molecule Grb2 to induce proliferation of myoblasts. In contrast, the actions of HGF on sensory neurons are mediated by Met effecters distinct from Grb2. Our findings demonstrate a requirement for Met signaling in neurons during development.