Ethanol disrupts axon outgrowth stimulated by netrin-1, GDNF, and L1 by blocking their convergent activation of Src family kinase signaling (Retracted article. See vol. 132, pg. 756, 2015)
Ethanol disrupts axon outgrowth stimulated by netrin-1, GDNF, and L1 by blocking their convergent activation of Src family kinase signaling (Retracted article. See vol. 132, pg. 756, 2015)
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DOI：
10.1111/j.1471-4159.2012.07954.x
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发表时间：
2012-11-01
影响因子：
4.7
通讯作者：
Charness, Michael E.
中科院分区：
文献类型：
--
作者：
Chen, Suzhen;Charness, Michael E.
产前酒精暴露会导致胎儿酒精谱障碍(FASD)，这是导致发育障碍的最常见、最可预防的原因。发育中的小脑特别容易受到乙醇的影响。我们报道乙醇通过阻断活性依赖神经保护蛋白(ADNP)的活性基序Fyn激酶及其下游信号分子支架蛋白Cas对NAP的激活来抑制NAP对小脑颗粒神经元(CGN)轴突生长的刺激作用。在这里，我们问乙醇是否通过对Src家族激酶(SFK)的共同作用来抑制不同轴突导向分子对轴突生长的刺激。我们首次证明了netrin-1、胶质细胞源性神经营养因子(GDNF)和神经细胞黏附分子L1通过激活SFK、Cas和细胞外信号调节激酶1和2(ERK1/2)来刺激CGN中的轴突生长。特异性的SFK抑制剂PP2阻断了这些轴突引导分子对轴突生长的刺激和对SFK-Cas-ERK1/2信号通路的激活。相反，脑源性神经营养因子(BDNF)刺激轴突生长并激活ERK1/2，而不先激活SFK或Cas。临床相关浓度的乙醇抑制Netrin-1、GDNF和L1诱导的轴突生长和SFK-Cas-ERK1/2通路的激活，但不阻断BDNF诱导的轴突生长或ERK1/2激活。这些结果表明，SFK而不是ERK1/2是乙醇抑制轴突生长的主要靶点。乙醇能够阻断Netrin-1、GDNF、L1和ADNP对SFK-Cas-ERK1/2通路的趋同激活，这可能在FASD的发病机制中起重要作用。
Pre-natal alcohol exposure causes fetal alcohol spectrum disorders (FASD), the most common, preventable cause of developmental disability. The developing cerebellum is particularly vulnerable to the effects of ethanol. We reported that ethanol inhibits the stimulation of axon outgrowth in cerebellar granule neurons (CGN) by NAP, an active motif of activity-dependent neuroprotective protein (ADNP), by blocking NAP activation of Fyn kinase and its downstream signaling molecule, the scaffolding protein Cas. Here, we asked whether ethanol inhibits the stimulation of axon outgrowth by diverse axon guidance molecules through a common action on the Src family kinases (SFK). We first demonstrated that netrin-1, glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule L1 stimulate axon outgrowth in CGNs by activating SFK, Cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The specific SFK inhibitor, PP2, blocked the stimulation of axon outgrowth and the activation of the SFK-Cas-ERK1/2 signaling pathway by each of these axon-guidance molecules. In contrast, brain-derived neurotrophic factor (BDNF) stimulated axon outgrowth and activated ERK1/2 without first activating SFK or Cas. Clinically relevant concentrations of ethanol inhibited axon outgrowth and the activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, and L1, but did not disrupt BDNF-induced axon outgrowth or ERK1/2 activation. These results indicate that SFK, but not ERK1/2, is a primary target for ethanol inhibition of axon outgrowth. The ability of ethanol to block the convergent activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, L1, and ADNP could contribute significantly to the pathogenesis of FASD.