Fibroblast growth factor receptor signaling in oligodendrocytes regulates myelin sheath thickness.
Fibroblast growth factor receptor signaling in oligodendrocytes regulates myelin sheath thickness.
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DOI：
10.1523/jneurosci.6005-11.2012
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发表时间：
2012-05-09
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影响因子：
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通讯作者：
Bansal R
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文献类型：
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作者：
Furusho M;Dupree JL;Nave KA;Bansal R
中枢神经系统（CNS）白色物质的形成在发育过程中受到严格的调控，但对出生后CNS中髓鞘形成控制的分子和机制知之甚少。在这里，我们表明，髓鞘的生长是由成纤维细胞生长因子（FGF）信号，最初确定为少突胶质细胞前体细胞（OPC）在体外的增殖信号。我们建立了两个少突胶质细胞系细胞中缺乏FGF受体1（Fgfr 1）和Fgfr 2的小鼠品系，但发现在这些小鼠中OPC增殖和分化不受影响。轴突鞘化和髓鞘形成的起始也是及时的。然而，中枢神经系统髓鞘的快速增长，通常发生在出生后第二周，强烈抑制。在整个成年期，髓鞘相对于轴突口径保持不成比例地薄。在成年小鼠中，突变少突胶质细胞的数量是正常的，而主要髓鞘基因的转录减少。这种FGF-受体介导的成熟少突胶质细胞的刺激也可以在体外建模，表明少突胶质细胞过程的增强扩增需要细胞外信号调节激酶-1和-2（Erk 1/2）（促分裂原活化蛋白激酶（MAPK）的下游介导物）的信号传导。同样在体内，Erk 1/2-MAPK活性在Fgfr 1/Fgfr 2突变小鼠的低髓鞘化CNS中降低。这些研究揭示了少突胶质细胞中FGF受体信号传导的一种以前未被认识的功能，该功能有助于髓鞘厚度的调节，并且将髓鞘形成的起始与髓鞘持续生长的后期相分离。
Formation of the central nervous system (CNS) white matter is developmentally tightly regulated, but the molecules and mechanisms of myelination control in the postnatal CNS are poorly understood. Here, we show that myelin growth is controlled by Fibroblast Growth Factor (FGF) signaling, originally identified as a proliferative signal for oligodendrocyte precursor cells (OPC) in vitro. We created two lines of mice lacking both FGF-receptor 1 (Fgfr1) and Fgfr2 in oligodendrocyte lineage cells but found that in these mice OPC proliferation and differentiation were unaffected. Also axonal ensheathment and the initiation of myelination was on time. However, the rapid growth of CNS myelin, normally occurring in the second postnatal week, was strongly inhibited. Throughout adulthood, the myelin sheath remained disproportionately thin relative to the axon caliber. In adult mice, mutant oligodendrocytes were normal in number, whereas the transcription of major myelin genes was reduced. This FGF-receptor mediated stimulation of mature oligodendrocytes could also be modeled in vitro, demonstrating that enhanced expansion of oligodendroglial processes requires signaling by extracellular-signal regulated kinases-1 and -2 (Erk1/2), downstream mediaters of Mitogen-Activated Protein Kinase (MAPK). Also in vivo, Erk1/2-MAPK activity was reduced in the hypomyelinated CNS of Fgfr1/Fgfr2 mutant mice. These studies reveal a previously unrecognized function of FGF-receptor signaling in oligodendrocytes that contributes to the regulation of myelin sheath thickness, and which uncouples the initiation of ensheathment from the later phase of continued myelin growth.