IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination
IRS-2 branch of IGF-1 receptor signaling is essential for appropriate timing of myelination
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DOI：
10.1111/j.1471-4159.2008.05631.x
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发表时间：
2008-11-01
影响因子：
4.7
通讯作者：
Schubert, Markus
中科院分区：
文献类型：
--
作者：
Freude, Susanna;Leeser, Uschi;Schubert, Markus
胰岛素样生长因子（IGF）-1促进少突胶质细胞及其前体细胞的增殖、抑制凋亡和促进分化，表明IGF-1受体（IGF-1 R）信号传导在髓鞘发育中的重要功能。胰岛素受体底物（IRS）IRS-1和IRS-2作为细胞内IGF-1 R衔接蛋白，在神经元、少突胶质细胞及其前体细胞中表达。为了阐明IRS-2在髓鞘形成中的作用，我们分析了IRS-2缺陷（IRS-2（-/-））小鼠和年龄匹配的对照小鼠在出生后发育过程中的髓鞘形成。有趣的是，与对照组相比，出生后第10天（P10）IRS-2（-/-）脑中最丰富的髓鞘蛋白、髓鞘碱性蛋白和蛋白脂质蛋白的表达减少。在P10-IRS-2（-/-）小鼠中，髓鞘碱性蛋白免疫染色显示免疫染色减少，但区域分布模式不变。在P10的脑髓鞘分离物中，发现不同髓鞘蛋白的相对表达没有改变，这表明髓鞘形成在数量上减少，但在质量上没有改变。有趣的是，在P10-14在IRS-2（-/-）小鼠中观察到IRS-1表达上调和IGF-1 R信号增加，表明克服IRS-2缺乏的代偿机制。成年IRS-2（-/-）小鼠表现出髓鞘形成和运动功能不变。此外，在神经元/脑特异性胰岛素受体敲除小鼠中，髓鞘形成没有变化。因此，我们的实验表明，IGF-1 R/IRS-2介导的信号是至关重要的适当时机的髓鞘在体内。
Insulin-like growth factor (IGF)-1 increases proliferation, inhibits apoptosis and promotes differentiation of oligodendrocytes and their precursor cells, indicating an important function for IGF-1 receptor (IGF-1R) signaling in myelin development. The insulin receptor substrates (IRS), IRS-1 and -2 serve as intracellular IGF-1R adaptor proteins and are expressed in neurons, oligodendrocytes and their precursors. To address the role of IRS-2 in myelination, we analyzed myelination in IRS-2 deficient (IRS-2(-/-)) mice and age-matched controls during postnatal development. Interestingly, expression of the most abundant myelin proteins, myelin basic protein and proteolipid protein was reduced in IRS-2(-/-) brains at postnatal day 10 (P10) as compared to controls. myelin basic protein immunostaining in P10-IRS-2(-/-) mice revealed a reduced immunostaining, but an unchanged regional distribution pattern. In cerebral myelin isolates at P10 unaltered relative expression of different myelin proteins was found, indicating quantitatively reduced but not qualitatively altered myelination. Interestingly, up-regulation of IRS-1 expression and increased IGF-1R signaling were observed in IRS-2(-/-) mice at P10-14, indicating a compensatory mechanism to overcome IRS-2 deficiency. Adult IRS-2(-/-) mice showed unaltered myelination and motor function. Furthermore, in neuronal/brain-specific insulin receptor knockout mice myelination was unchanged. Thus, our experiments reveal that IGF-1R/IRS-2 mediated signals are critical for appropriate timing of myelination in vivo.