Zeger Martha, Popken Greg, Zhang Jihui, Xuan Shouhong, Lu Q Richard, Schwab Markus H, Nave Klaus-Armin, Rowitch David, D'Ercole A Joseph, Ye Ping
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7039, USA.
Glia. 2007 Mar;55(4):400-11. doi: 10.1002/glia.20469.
Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R(pre-oligo-ko) and IGF1R(oligo-ko) mice, respectively). Compared with wild type mice, IGF1R(pre-oligo-ko) mice had a decreased volume (by 35-55%) and cell number (by 54-70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R(oligo-ko) mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2(+) oligodendrocyte precursors was decreased by approximately 13% in 2-week-old IGF1R(pre-oligo-ko) mice, while the percentage of CC1(+) mature oligodendrocytes was decreased by approximately 24% in 6-week-old IGF1R(pre-oligo-ko) mice and approximately 25% in 25-week-old IGF1R(oligo-ko) mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.
胰岛素样生长因子-I（IGF-I）已被证明是促进少突胶质前体细胞生长和分化以及在发育过程和损伤后刺激髓鞘形成的有效因子。为了明确确定IGF-I是否直接作用于少突胶质细胞系的细胞，我们构建了小鼠品系，其中1型IGF受体基因（igf1r）在Olig1或表达蛋白脂蛋白的细胞中被条件性敲除（分别称为IGF1R（少突胶质前体细胞敲除）和IGF1R（少突胶质细胞敲除）小鼠）。与野生型小鼠相比，IGF1R（少突胶质前体细胞敲除）小鼠在2周龄和6周龄时，胼胝体（CC）和前连合的体积分别减少了35 - 55%，细胞数量分别减少了54 - 70%。到25周龄时，IGF1R（少突胶质细胞敲除）小鼠的CC体积和细胞数量也有所减少，尽管不太明显。与星形胶质细胞不同，2周龄的IGF1R（少突胶质前体细胞敲除）小鼠中NG2(+)少突胶质前体细胞的百分比降低了约13%，而6周龄的IGF1R（少突胶质前体细胞敲除）小鼠中CC1(+)成熟少突胶质细胞的百分比降低了约24%，25周龄的IGF1R（少突胶质细胞敲除）小鼠中降低了约25%。这些细胞数量的减少显然是增殖减少和凋亡增加的结果。这些结果表明，IGF-I通过IGF1R在体内直接影响少突胶质细胞和髓鞘形成，并且少突胶质细胞系细胞中的IGF1R信号传导是正常少突胶质细胞发育和髓鞘形成所必需的。这些数据也为开发有可能靶向少突胶质细胞系细胞中IGF-IGF1R信号通路治疗脱髓鞘疾病的策略提供了基础。
