Ye Ping, Li Liqin, Lund P Kay, D'Ercole A Joseph
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Brain Res Dev Brain Res. 2002 Jun 30;136(2):111-21. doi: 10.1016/s0165-3806(02)00355-3.
To determine whether insulin receptor substrate-1 (IRS-1) is essential in mediating insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination in vivo, we cross-bred IGF-I transgenic (Tg) mice with IRS-1 null mutant (IRS-1(-/-)) mice and examined brain growth and expression of myelin-specific proteins in mice that overexpress IGF-I with or without IRS-1 expression. We found that while IGF-I overexpression stimulates a dramatic increase in brain weight (43%) by 7-8 weeks of age in the absence of IRS-1, it stimulates a greater increase (50%) with intact IRS-1 expression. To evaluate myelination we investigated IGF-I-stimulated expression of myelin basic protein (MBP) and proteolipid protein (PLP) in the cerebral cortex CTX and brainstem, and found similar increases in each region in IRS-1(-/-) and wild type mice. In studies using mixed glial cultures derived from IRS-1(-/-) mice, IGF-I also increased the abundance of MBP and PLP mRNA. To assess possible alternate mediators of IGF-I actions, we examined IRS-2 and IRS-4 and found that the abundance of each is increased in the CTX of IRS-1(-/-) mice and IGF-I Tg mice. Our results suggest that IRS-1 is not essential in IGF-I promotion of oligodendrocyte development and myelination, and that IRS-2 and IRS-4 may compensate for the loss of IRS-1 expression and function in the cells of oligodendrocyte lineage. Nonetheless, the finding that IGF-I stimulates brain growth less well in the absence of IRS-1 suggests that IRS-1-mediated signaling may be more central to IGF-I action in cells other than glia and oligodendrocytes.
为了确定胰岛素受体底物-1（IRS-1）在介导胰岛素样生长因子-I（IGF-I）刺激体内脑生长和髓鞘形成中是否必不可少，我们将IGF-I转基因（Tg）小鼠与IRS-1基因敲除突变体（IRS-1(-/-)）小鼠进行杂交，并检查了在有或没有IRS-1表达的情况下过表达IGF-I的小鼠的脑生长和髓鞘特异性蛋白的表达。我们发现，虽然在没有IRS-1的情况下，IGF-I的过表达在7-8周龄时会刺激脑重量显著增加（43%），但在IRS-1表达完整的情况下，它会刺激更大幅度的增加（50%）。为了评估髓鞘形成，我们研究了IGF-I刺激的大脑皮层（CTX）和脑干中髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）的表达，发现在IRS-1(-/-)小鼠和野生型小鼠的每个区域中都有类似的增加。在使用源自IRS-1(-/-)小鼠的混合神经胶质细胞培养物的研究中，IGF-I也增加了MBP和PLP mRNA的丰度。为了评估IGF-I作用的可能替代介质，我们检查了IRS-2和IRS-4，发现它们在IRS-1(-/-)小鼠和IGF-I Tg小鼠的CTX中的丰度均增加。我们的结果表明，IRS-1在IGF-I促进少突胶质细胞发育和髓鞘形成中并非必不可少，并且IRS-2和IRS-4可能补偿少突胶质细胞谱系细胞中IRS-1表达和功能的丧失。尽管如此，在没有IRS-1的情况下IGF-I刺激脑生长效果较差这一发现表明，IRS-1介导的信号传导可能在IGF-I作用于神经胶质细胞和少突胶质细胞以外的细胞中更为关键。
