FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c‐Jun axis
FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c‐Jun axis
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DOI：
10.1002/jcp.29942
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发表时间：
2020-07
影响因子：
5.6
通讯作者：
Yunzhong Zhang;Ketao Jiang;Guoqing Xie;Jie Ding;S. Peng;Xiaoyu Liu;Cheng Sun;Xin Tang
中科院分区：
文献类型：
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作者：
Yunzhong Zhang;Ketao Jiang;Guoqing Xie;Jie Ding;S. Peng;Xiaoyu Liu;Cheng Sun;Xin Tang
成纤维细胞生长因子21 （Fibroblast growth factor 21, FGF21）是一种代谢应激激素，主要由肝脏分泌。除了其在能量稳态中的明确作用外，FGF21已被证明可促进中枢神经系统损伤后的髓鞘再生。在当前的研究中，我们试图研究FGF21在周围神经系统（PNS）髓鞘形成中的潜在作用。在PNS髓磷脂发育过程中，Fgf21表达与髓磷脂基因表达呈负相关。在培养的原代雪旺细胞（SCs）中，重组FGF21的应用大大降低了髓鞘形成相关基因的表达，包括Oct6、Krox20、Mbp、Mpz和Pmp22。因此，新生大鼠注射FGF21可明显减轻坐骨神经髓鞘形成。相反，注入抗FGF21抗体可加速髓鞘形成。在机制上，FGF21刺激sc和坐骨神经中的细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）。包括药物干预和基因操作在内的后续实验表明，FGF21靶向p38 MAPK/c‐Jun轴，而不是ERK，介导其对sc中髓鞘形成的抑制。综上所述，我们的数据提供了FGF21的一个新方面，通过激活p38 MAPK/c‐Jun， FGF21作为PNS中髓磷脂发育过程的负调节因子。
Fibroblast growth factor 21 (FGF21) as a metabolic stress hormone, is mainly secreted by the liver. In addition to its well‐defined roles in energy homeostasis, FGF21 has been shown to promote remyelination after injury in the central nervous system. In the current study, we sought to examine the potential roles of FGF21 in the peripheral nervous system (PNS) myelination. In the PNS myelin development, Fgf21 expression was reversely correlated with myelin gene expression. In cultured primary Schwann cells (SCs), the application of recombinant FGF21 greatly attenuates myelination‐associated gene expression, including Oct6, Krox20, Mbp, Mpz, and Pmp22. Accordingly, the injection of FGF21 into neonatal rats markedly mitigates the myelination in sciatic nerves. On the contrary, the infusion of the anti‐FGF21 antibody accelerates the myelination. Mechanistically, both extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein kinase (MAPK) were stimulated by FGF21 in SCs and sciatic nerves. Following experiments including pharmaceutical intervention and gene manipulation revealed that the p38 MAPK/c‐Jun axis, rather than ERK, is targeted by FGF21 for mediating its repression on myelination in SCs. Taken together, our data provide a new aspect of FGF21 by acting as a negative regulator for the myelin development process in the PNS via activation of p38 MAPK/c‐Jun.