Disruption of Fibroblast Growth Factor Receptor Signaling in Nonmyelinating Schwann Cells Causes Sensory Axonal Neuropathy and Impairment of Thermal Pain Sensitivity
Disruption of Fibroblast Growth Factor Receptor Signaling in Nonmyelinating Schwann Cells Causes Sensory Axonal Neuropathy and Impairment of Thermal Pain Sensitivity
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DOI：
10.1523/jneurosci.5615-08.2009
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发表时间：
2009-02-11
影响因子：
5.3
通讯作者：
Bansal, Rashmi
中科院分区：
文献类型：
--
作者：
Furusho, Miki;Dupree, Jeffrey L.;Bansal, Rashmi
轴突-神经胶质相互作用对于周围神经的正常功能至关重要，其破坏会导致周围神经病。成纤维细胞生长因子（FGF）是损伤后周围神经再生的关键因素。我们研究了 FGF 受体 (Fgfr) 信号在雪旺细胞中的作用以及正常雪旺细胞-轴突相互作用的后续调节。在转基因小鼠的有髓鞘和非髓鞘雪旺细胞 (NMSC) 中，Fgfr1 和 Fgfr2 单独或组合条件失活。双突变小鼠表现出热敏感性显着丧失，并伴有终止于脊髓背角的无髓鞘伤害性感觉轴突的明显神经病变，脊髓背角是整合疼痛和温度输入的主要部位。在坐骨神经 Remak 束的伤害性 C 纤维中也观察到神经病变，尽管程度较轻；然而，包裹这些轴突的 NMSC 并没有损失。此外，由有髓鞘雪旺细胞和相关髓鞘包裹的轴突似乎不受影响。相对于双突变体，Fgfr1 而非 Fgfr2 单突变体的轴突神经病变发生得晚得多，这表明两种受体的信号传导潜力存在差异，Fgfr1 比 Fgfr2 更强大。这些发现强调了 Fgfr1 和 Fgfr2 信号传导作为外周感觉疼痛通路中轴突-神经胶质相互作用的潜在介质的重要性，主要通过影响 NMSC 功能，进而调节无髓鞘感觉轴突的结构和功能。这项研究提供了一种新的伤害感受分子机制，可能对周围感觉神经病的疼痛敏感性产生影响。
Axon-glial interactions are critical for normal functioning of peripheral nerves, and their disruption leads to peripheral neuropathies. Fibroblast growth factors (FGFs) are key players in peripheral nerve regeneration after injury. We investigated the role of FGF receptor (Fgfr) signaling in Schwann cells and the consequent regulation of normal Schwann cell-axon interactions. Fgfr1 and Fgfr2 were conditionally inactivated, either singly or in combination, in myelinating and nonmyelinating Schwann cells (NMSCs) of transgenic mice. The double mutant mice displayed significant loss of thermal sensitivity accompanied by marked neuropathy of unmyelinated nociceptive sensory axons terminating in the dorsal horn of spinal cords, the primary site for integrating pain and temperature inputs. Neuropathy, although to a lesser extent, was also observed in the nociceptive C-fibers in the Remak bundles of sciatic nerves; however, there was no loss of NMSCs that ensheathe these axons. Furthermore, axons wrapped by myelinating Schwann cells and associated myelin sheaths appeared to be unaffected. Relative to the double mutants, axonal neuropathy developed much later in the Fgfr1 but not Fgfr2 single mutant, indicating a difference in signaling potential of the two receptors, with Fgfr1 being more robust than Fgfr2. These findings emphasize the importance of Fgfr1 and Fgfr2 signaling as potential mediators of axon-glial interaction in the peripheral sensory pain pathway primarily via influencing NMSC function, which in turn modulates the structure and function of unmyelinated sensory axons. This study provides a novel molecular mechanism for nociception with possible implications for pain sensitivity in peripheral sensory neuropathies.