Ethanol alters BDNF-induced Rho GTPase activation in axonal growth cones.
Ethanol alters BDNF-induced Rho GTPase activation in axonal growth cones.
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DOI：
10.1111/j.1530-0277.2011.01468.x
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Ruggiero EA
中科院分区：
文献类型：
--
作者：
Lindsley TA;Shah SN;Ruggiero EA
乙醇对有丝分裂后神经元发育的影响包括神经突生长和分化的改变，这可能导致与胎儿酒精谱系障碍相关的神经病理学。我们以前报道，乙醇暴露改变轴突生长动力学在大鼠海马锥体神经元分离培养。鉴于小Rho GTPases在与轴突生长相关的细胞骨架重组中的重要调节作用，以及乙醇改变其他细胞类型中的全细胞Rho GTPases活性的报道，本研究探讨了乙醇改变Rho GTPases活性的假设，特别是在轴突生长锥中。将胎鼠海马锥体神经元在对照培养基或含有11-43 mM乙醇的培养基中的解离培养物中维持1天。一些培养物也用脑源性神经营养因子（BDNF）处理，BDNF是Rac 1和Cdc 42 GTP酶的激活剂，可促进轴突延伸。生长锥中的活性Rho GTPases的水平使用GTP结合Rac 1，Cdc 42和RhoA的原位结合测定来测量。轴突长度，生长锥面积和生长锥表面表达的TrkB，BDNF的受体，通过数字形态计量学和免疫细胞化学进行了评估。虽然乙醇增加了生长锥的表面积，但在没有外源性BDNF的情况下，轴突生长锥中活性Rho GTPases的水平不受影响。与此相反，乙醇暴露抑制BDNF诱导的Rac 1/Cdc 42激活的剂量依赖性的方式和增加RhoA激活在最高浓度的测试。在对照组和乙醇处理组神经元的轴突生长锥表面上观察到类似的TrkB表达。这些结果揭示了生长锥信号通过小Rho GTPases在体外海马发育的早期阶段，乙醇的抑制作用，并提出了一种机制，乙醇可能会破坏轴突生长和指导神经营养因子的调节。
The effects of ethanol on development of postmitotic neurons include altered neurite outgrowth and differentiation, which may contribute to neuropathology associated with fetal alcohol spectrum disorders. We previously reported that ethanol exposure alters axon growth dynamics in dissociated cultures of rat hippocampal pyramidal neurons. Given the important regulatory role of small Rho GTPases in cytoskeletal reorganization associated with axon growth, and reports that ethanol alters whole cell Rho GTPase activity in other cell types, this study explored the hypothesis that ethanol alters Rho GTPase activity specifically in axonal growth cones. Fetal rat hippocampal pyramidal neurons were maintained in dissociated cultures for 1 day in control medium or medium containing 11-43 mM ethanol. Some cultures were also treated with brain-derived neurotrophic factor (BDNF), an activator of Rac1 and Cdc42 GTPases that promotes axon extension. Levels of active Rho GTPases in growth cones were measured using in situ binding assays for GTP-bound Rac1, Cdc42 and RhoA. Axon length, growth cone area and growth cone surface expression of TrkB, the receptor for BDNF, were assessed by digital morphometry and immunocytochemistry. Although ethanol increased the surface area of growth cones, the levels of active Rho GTPases in axonal growth cones were not affected in the absence of exogenous BDNF. In contrast, ethanol exposure inhibited BDNF-induced Rac1/Cdc42 activation in a dose-dependent manner and increased RhoA activation at the highest concentration tested. Similar TrkB expression was observed on the surface of axonal growth cones of control and ethanol-treated neurons. These results reveal an inhibitory effect of ethanol on growth cone signaling via small Rho GTPases during early stages of hippocampal development in vitro, and suggest a mechanism whereby ethanol may disrupt neurotrophic factor regulation of axon growth and guidance.
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DOI：
10.1016/j.bbrc.2004.11.151
发表时间：
2005-02-04
影响因子：
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