The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons.
The insulin-like growth factor 1 receptor is essential for axonal regeneration in adult central nervous system neurons.
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DOI：
10.1371/journal.pone.0054462
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Quiroga S
中科院分区：
文献类型：
--
作者：
Dupraz S;Grassi D;Karnas D;Nieto Guil AF;Hicks D;Quiroga S
轴突再生是损伤成人中枢神经系统（CNS）重建功能性神经元连接的必要条件，但断裂轴突的有效再生已被证明是非常困难的。虽然在确定所涉及的内在和外在机制方面取得了重大进展，但许多方面仍未解决。胚胎中枢神经系统（海马）轴突发育需要胰岛素样生长因子1受体（IGF-1R）的专性激活。基于已知的胎儿与成熟中枢神经系统轴突生长之间的相似性，我们决定在成人中枢神经系统轴突再生的体外模型中，即来自成年大鼠视网膜的视网膜神经节细胞（RGC）中，使用针对βgc亚基的抗体或针对IGF-R （C20）的多克隆抗肽抗体，检测IGF-1R的表达。在新鲜分离的成年RGC中，βgc和C20抗体识别的β亚基的表达均较低，但在体外4天后显著升高。与胚胎轴突一样，在RGC中，βgc定位于远端区域和主要生长锥。IGF-1R-βgc与活化的p85共定位，在IGF-1刺激下参与磷脂酰肌醇-3激酶（PI3K）信号通路。使用中和IGF-1R激活的抗体、针对IGF-1R序列设计的shRNA或PI3K途径抑制剂LY294002进行阻断实验，均显著降低体外成人RGC的轴突再生（对照组中约40%的RGC具有轴突，而不同阻断研究中为2-8%）。最后，将RGC与shRNA共转染以沉默IGF-1R，并与含有组成活性形式的下游PI3K （p110）的载体一起，在体外完全恢复轴突生长。因此，这些数据表明，成人中枢神经系统神经元的轴突再生需要IGF-1R的重新表达和激活，并且针对该系统可能为促进创伤后轴突再生提供新的治疗方法。
Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). Based on known similarities between axonal growth in fetal compared to mature CNS, we decided to examine the expression of the IGF-1R, using an antibody to the βgc subunit or a polyclonal anti-peptide antibody directed to the IGF-R (C20), in an in vitro model of adult CNS axonal regeneration, namely retinal ganglion cells (RGC) derived from adult rat retinas. Expression of both βgc and the β subunit recognized by C20 antibody were low in freshly isolated adult RGC, but increased significantly after 4 days in vitro. As in embryonic axons, βgc was localised to distal regions and leading growth cones in RGC. IGF-1R-βgc co-localised with activated p85 involved in the phosphatidylinositol-3 kinase (PI3K) signaling pathway, upon stimulation with IGF-1. Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2–8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma.
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DOI：
10.1007/978-0-387-76715-4_1
发表时间：
2007-01-01
期刊：
AXON GROWTH AND GUIDANCE
影响因子：
--
作者：
Bouquet, Celine;Nothias, Fatiha
通讯作者：
Nothias, Fatiha
影响因子：
1.7
作者：
Akahori, Y;Horie, H
通讯作者：
Horie, H
影响因子：
4.6
作者：
Kim, Ju Young;Schafer, Julie;Ming, Guo-li
通讯作者：
Ming, Guo-li
影响因子：
2.9
作者：
Bonnet, D;Garcia, M;Hicks, D
通讯作者：
Hicks, D
影响因子：
3.4
作者：
Buffo, A;Carulli, D;Strata, P
通讯作者：
Strata, P