当前位置: X-MOL 学术Acta Neuropathol. Commun. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential.
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2019-12-19 , DOI: 10.1186/s40478-019-0864-6
Katja Thümmler 1 , Eran Rom 2 , Thomas Zeis 3 , Maren Lindner 1 , Sarah Brunner 3 , John J Cole 1 , Diana Arseni 1 , Steve Mücklisch 4 , Julia M Edgar 1 , Nicole Schaeren-Wiemers 3 , Avner Yayon 2 , Christopher Linington 1
Affiliation  

Fibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.

中文翻译:

极化受体激活将成纤维细胞生长因子2介导的髓鞘形成抑制从其神经保护能力中解离出来。

成纤维细胞生长因子(FGF)信号传导会导致多发性硬化症的髓鞘再生失败,但以治疗为目标的功能性多效性使其变得复杂。现在,我们确定FGF2是星形胶质细胞在活跃的炎症性病变中上调的因子,该炎症性病变通过FGF受体2(FGFR2)介导的Wingless(Wnt)信号传导破坏髓鞘形成;Wnt的药理学抑制作用足以消除组织培养物中FGF2对髓鞘形成的抑制作用。使用通过删除FGF2 N末端26个氨基酸而产生的新型FGFR1选择性激动剂(F2 V2),我们证明了极化信号转导有利于FGFR1消除了FGF介导的髓鞘抑制,但保留了其诱导促髓鞘和免疫调节表达的能力。这些因素包括Cd93,Lif,Il11,Hbegf,Cxcl1和Timp1。
更新日期:2019-12-20
down
wechat
bug