Inhibition of insulin-like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: in vitro analysis.
Inhibition of insulin-like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: in vitro analysis.
复制标题
胰岛素样生长因子 I 活性的抑制导致 weaver 突变小鼠小脑颗粒神经元过早凋亡：体外分析。
DOI：
10.1002/jnr.10360
复制
发表时间：
2002
影响因子：
4.2
通讯作者：
Lee,Wei-Hua
中科院分区：
文献类型：
--
作者：
Zhong,Jin;Deng,Jixian;Ghetti,Bernardino;Lee,Wei-Hua
来自转基因小鼠和培养的小脑神经元的证据支持胰岛素样生长因子I （IGF - I）在小脑细胞结构形成中的重要作用。为了了解IGF - I在小脑发育过程中的功能，我们研究了IGF - I在weaver （wv）突变小鼠小脑颗粒神经元过早凋亡中的作用。在死亡之前，wv颗粒神经元以基因剂量依赖性的方式增加了IGFBP5的表达和分泌。由于IGFBP5可能干扰IGF - I及其受体的相互作用，颗粒神经元中异常高的IGFBP5水平表明缺乏IGF - I激活可能导致其过早凋亡。IGF - I受体（IGF - IR）磷酸化的基因剂量依赖性降低支持了这一假设。更重要的是，Akt活性呈平行基因剂量依赖性下降，这与caspase 3的活性水平呈负相关。另一方面，在培养液中添加IGFBP5抗体可提高野生型颗粒神经元的存活率，而添加IGFBP5抗体可降低野生型颗粒神经元的存活率。为了描述IGF - I和IGFBP5对颗粒神经元的相互作用，我们检测了用IGF - I、des(1-3) IGF - I或IGFBP5抗体治疗后的神经元存活率。在相同浓度下，des(1-3) IGF - I在促进存活、提高Akt活性和降低caspase 3活性方面比IGF - I更有效。这些结果表明，IGF - I对颗粒神经元的作用通常被过量的IGFBP5抑制，而足够的IGF - I受体激活通过刺激Akt信号通路来拯救颗粒神经元。©2002 Wiley‐Liss, Inc。
Evidence from transgenic mice and cultured cerebellar neurons supports an important role for insulin‐like growth factor I (IGF‐I) in the formation of cerebellar cytoarchitecture. To understand IGF‐I's function during cerebellar development, we examined the involvement of IGF‐I in the premature apoptosis of granule neurons derived from the cerebella of weaver (wv) mutant mice. Before their demise,wvgranule neurons increased the expression and secretion of IGFBP5 in a gene dose‐dependent manner. Because IGFBP5 may interfere with the interaction of IGF‐I and its receptor, the abnormally high IGFBP5 levels inwvgranule neurons suggest that a lack of IGF‐I activation may contribute to their premature apoptosis. This hypothesis is supported by a gene dose‐dependent decrease in IGF‐I receptor (IGF‐IR) phosphorylation. More importantly, there is a parallel gene dose‐dependent decrease in Akt activity, which was inversely correlated with the activity levels of caspase 3. On the other hand, adding IGFBP5 antibody into culture media increased the survival ofwvgranule neurons, whereas adding IGFBP5 decreased the survival of wild‐type granule neurons. To delineate the interaction between IGF‐I and IGFBP5 onwvgranule neurons, we examined neuronal survival after treating with IGF‐I, des(1–3) IGF‐I, or IGFBP5 antibody. At the same concentration, des(1–3) IGF‐I was more effective than IGF‐I in promoting survival, in increasing Akt activity, and in decreasing caspase 3 activity. These results indicate that IGF‐I's actions onwvgranule neurons are normally inhibited by excess IGFBP5, and sufficient IGF‐I receptor activation rescueswvgranule neurons via stimulating the Akt signaling pathway. © 2002 Wiley‐Liss, Inc.