Furusho Miki, Ishii Akihiro, Bansal Rashmi
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030.
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut 06030
J Neurosci. 2017 Mar 15;37(11):2931-2946. doi: 10.1523/JNEUROSCI.3316-16.2017. Epub 2017 Feb 13.
FGF signaling has emerged as a significant "late-stage" regulator of myelin thickness in the CNS, independent of oligodendrocyte differentiation. Therefore, it is critically important to identify the specific FGF receptor type and its downstream signaling molecules in oligodendrocytes to obtain better insights into the regulatory mechanisms of myelin growth. Here, we show that FGF receptor type 2 (FGFR2) is highly enriched at the paranodal loops of myelin. Conditional ablation of this receptor-type, but not FGF receptor type 1 (FGFR1), resulted in attenuation of myelin growth, expression of major myelin genes, key transcription factor Myrf and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) activity. This was rescued by upregulating ERK1/2 activity in these mice, strongly suggesting that ERK1/2 are key transducers of FGFR2 signals for myelin growth. However, given that the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway is also known to regulate myelin thickness, we examined FGFR2-deficient mice for the expression of key signaling molecules in this pathway. A significant downregulation of p-mTOR, p-Raptor, and p-S6RP was observed, which was restored to normal by elevating ERK1/2 activity in these mice. Similar downregulation of these molecules was observed in ERK1/2 knock-out mice. Interestingly, since p-Akt levels remained largely unchanged in these mice, it suggests a mechanism of mTORC1 activation by ERK1/2 in an Akt-independent manner in oligodendrocytes. Taken together, these data support a model in which FGFs, possibly from axons, activate FGFR2 in the oligodendrocyte/myelin compartment to increase ERK1/2 activation, which ultimately targets Myrf, as well as converges with the PI3K/Akt/mTOR pathway at the level of mTORC1, working together to drive the growth of the myelin sheath, thus increasing myelin thickness. It is well accepted that myelin is a biologically active membrane in active communication with the axons. However, the axonal signals, the receptors on myelin, and the integration of intracellular signaling pathways emanating downstream from these receptors that drive the growth of the myelin sheath remain poorly understood in the CNS. This study brings up the intriguing possibility that FGF receptor 2, in the oligodendrocyte/myelin compartment, may be one such signal. Importantly, it provides compelling evidence linking FGFR2 with the ERK1/2-MAPK pathway, which converges with the PI3K/Akt/mTOR (mechanistic target of rapamycin) pathway at the level of mTORC1 and also regulates the transcription factor Myrf, together providing a mechanistic framework for regulating both the transcriptional and translational machinery required for the proper growth of the myelin sheath.
成纤维细胞生长因子（FGF）信号传导已成为中枢神经系统中髓鞘厚度的重要“晚期”调节因子，与少突胶质细胞分化无关。因此，确定少突胶质细胞中特定的FGF受体类型及其下游信号分子对于更好地了解髓鞘生长的调节机制至关重要。在此，我们表明2型FGF受体（FGFR2）在髓鞘的结旁环高度富集。条件性敲除该受体类型而非1型FGF受体（FGFR1），导致髓鞘生长、主要髓鞘基因表达、关键转录因子Myrf以及细胞外信号调节蛋白激酶1和2（ERK1/2）活性减弱。通过上调这些小鼠的ERK1/2活性可挽救这种情况，这强烈表明ERK1/2是FGFR2信号促进髓鞘生长的关键转导因子。然而，鉴于已知磷脂酰肌醇-3激酶/蛋白激酶B/雷帕霉素靶蛋白（PI3K/Akt/mTOR）途径也调节髓鞘厚度，我们检测了FGFR2缺陷小鼠中该途径关键信号分子的表达。观察到p-mTOR、p-Raptor和p-S6RP显著下调，通过提高这些小鼠的ERK1/2活性可恢复至正常水平。在ERK1/2基因敲除小鼠中也观察到这些分子的类似下调。有趣的是，由于这些小鼠中p-Akt水平基本保持不变，这表明在少突胶质细胞中ERK1/2以不依赖Akt的方式激活mTORC1。综上所述，这些数据支持一个模型，即FGFs（可能来自轴突）在少突胶质细胞/髓鞘区室中激活FGFR2以增加ERK1/2活性，最终作用于Myrf，并在mTORC1水平与PI3K/Akt/mTOR途径汇聚，共同驱动髓鞘的生长，从而增加髓鞘厚度。人们普遍认为髓鞘是一种与轴突进行活跃通信的生物活性膜。然而，在中枢神经系统中，轴突信号、髓鞘上的受体以及这些受体下游驱动髓鞘生长的细胞内信号通路的整合仍知之甚少。本研究提出了一个有趣的可能性，即少突胶质细胞/髓鞘区室中的FGF受体2可能是这样一种信号。重要的是，它提供了令人信服的证据将FGFR2与ERK1/2-丝裂原活化蛋白激酶（MAPK）途径联系起来，该途径在mTORC1水平与PI3K/Akt/mTOR（雷帕霉素靶蛋白）途径汇聚，并且还调节转录因子Myrf，共同为调节髓鞘正常生长所需的转录和翻译机制提供了一个机制框架。
