Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway
Hepatocyte growth factor and c-Met promote dendritic maturation during hippocampal neuron differentiation via the Akt pathway
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DOI：
10.1016/j.cellsig.2007.12.013
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发表时间：
2008-05-01
影响因子：
4.8
通讯作者：
Walikonis, Randall S.
中科院分区：
文献类型：
--
作者：
Lim, Chol Seung;Walikonis, Randall S.
在中枢神经系统发育过程中，生长因子及其相关的受体蛋白酪氨酸激酶调节许多神经元功能，如突起伸展和树突成熟。肝细胞生长因子(HGF)及其受体c-Met可以促进成熟神经元突起的形成和树突的形成，但它们对海马神经元树突成熟早期的影响以及促进树突形成的信号通路尚未见报道。外源性HGF可显著增强体外培养的海马神经元c-Met的磷酸化和活化。HGF处理增加了这些神经元的树突数目，并促进了树突的伸长。与这些结果一致的是，HGF激活Akt，使糖原合成酶-3β(GSK-3β)磷酸化以使其失活，并减少微管相关蛋白2(MAP2)的磷酸化，从而在去磷酸化时促进微管聚合和树突延长。相反，c-Met与其特异性抑制剂PHA-665752的药理抑制或c-Met与短发夹状RNA(ShRNAs)的基因敲除可抑制肝细胞生长因子诱导的Akt和GSK-3β的磷酸化，增加MAP2的磷酸化，并减少培养的海马神经元树突的数量和长度。此外，用PHA-665752或shRNA抑制c-Met可降低MAP2的表达。用磷酸化肌醇3-激酶抑制剂LY294002或Akt抑制剂X抑制Akt活性可抑制HGF诱导的GSK-3β的磷酸化，增加MAP2的磷酸化，并阻断HGF增加树突状细胞长度的能力。这些观察表明，HGF和c-Met可以通过激活Akt/GSK-3β途径来调节树突成熟的早期阶段。(C)2008 Elsevier Inc.保留所有权利。
During central nervous system development, growth factors and their associated receptor protein tyrosine kinases regulate many neuronal functions such as neurite extension and dendrite maturation. Hepatocyte growth factor (HGF) and its receptor, c-Met, can promote formation of neurites and enhance elaboration of dendrites in mature neurons, but their effects on the early stages of dendrite maturation in hippocampal neurons and the signaling pathways by which they promote dendrite formation have not been studied. Exogenous HGF treatment effectively enhanced the phosphorylation and activation of c-Met in cultured hippocampal neurons at 4 days in vitro. HGF treatment increased the number of dendrites and promoted dendrite elongation in these neurons. Consistent with these results, HGF activated Akt, which phosphorylates glycogen synthase kinase-3 beta (GSK-3 beta) to inactivate it, and reduced phosphorylation of microtubule-associated protein 2 (MAP2), which can promote microtubule polymerization and dendrite elongation when dephosphorylated. Conversely, pharmacological inhibition of c-Met with its specific inhibitor, PHA-665752, or genetic knock-down of c-Met with short hairpin RNAs (shRNAs) suppressed HGF-induced phosphorylation of Akt and GSK-3 beta, increased phosphorylation of MAP2, and reduced dendrite number and length in cultured hippocampal neurons. Moreover, suppressing c-Met with PHA-665752 or by shRNA decreased MAP2 expression. Inhibiting Akt activity with the phosphomositide-3-kinase inhibitor LY294002 or Akt inhibitor X suppressed HGF-induced phosphorylation of GSK-3 beta, increased MAP2 phosphorylation, and blocked the ability of HGF to enhance dendritic length. These observations indicate that HGF and c-Met can regulate the early stages of dendrite maturation via activation of the Akt/GSK-3 beta pathway. (C) 2008 Elsevier Inc. All rights reserved.