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Inhibition of neurite outgrowth using comme(5)
Myelin-associated inhibitors of nerve growth include three major molecules: MAG, Nogo-A (Nogo-66), and oligodendrocyte myelin glycoprotein (Filbin, 2003). MAG was the first myelin-derived growth inhibitory protein to be identified, and its inhibitory activity on nerve growth was elucidated in 1994 independently by both the Filbin lab and the McKerracher lab using cell-based and biochemical techniques, respectively (McKerracher and Rosen, 2015). MAG is a transmembrane glycoprotein produced by myelinating glial cells (including oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system)with a higher expression level in the central nervous system(Mukhopadhyay et al., 1994). MAG has been widely used as an inhibitory substrate for neurite growth assays using postnatal and adult neurons (Quarles, 2007). The MAG-Fc used in this study is a commercial product formed by the fusion of MAG with the Fc moiety of human immunoglobulin (Li et al., 2009). Because of its increase in molecular weight and the structural difference between MAG and MAG-Fc fragment,their bioactive properties might not be identical. Here, we show that MAG-Fc imitated the activity of MAG and has the same inhibitory effect on neurite out-growth as MAG. It also interacted mainly with NgR, a receptor complex for MAG,which consists of NgR, LINGO1/TROY, P75NTR and ganglioside GT1b (Domeniconi et al., 2002; Saha et al., 2014). The increased immuno fluorescence of NgR after incubation with MAG-Fc for 1 hour may be an effect of MAG on NgR expression, or facilitation of NgR raft/clustering on the membrane.
Both NgR and PirB are specific receptors of MAG (Domeniconi et al., 2002; Wang et al., 2002; Atwal et al., 2008; Filbin, 2008). The binding of MAG and NgR is key to initiating intracellular signaling pathways (Skaper, 2005) and MAGFc was able to magnify intracellular signaling strongly associated with the specific receptor complex. Many studies have shown that RhoA/ROCK is one of the main intracellular signaling pathways for NgR (Linseman and Loucks, 2008;Palandri et al., 2015). RhoA is a guanine triphosphatase. The binding of MAG to the NgR complex enables RhoA-GDP to convert to the activated form, RhoA-guanine triphosphatase. Activated RhoA subsequently initiates the phosphory-lation of Rho kinase, resulting in growth cone collapse and axonal growth repulsion (Yamashita and Tohyama, 2003).The inhibitory signal from MAG binding to PirB may also be transduced through the Rho-ROCK signaling pathway (Wang et al., 2012). The present study confirmed the existence of the specific receptors of myelin-associated inhibitors on neuro-2a cells. Meanwhile, the maximal endocytosis of MAG-Fc was observed after 50 minutes of adding MAG-Fc. The treatment of neuro-2a cells with MAG-Fc activated RhoA/ROCK signaling and displayed obvious inhibition on neurite high expression levels of NgR and PirB in neuro-2a cells also provide the structural basis by which exogenous MAGFc affects neurite outgrowth in these cells. However, the results from this study on the role of commercial MAG-Fc on neurite growth and its effect on the relevant intracellular signal pathways need to be verified further.
In summary, MAG-Fc can be used as a substitute for endogenous MAG to investigate the intracellular molecular events of myelin-associated inhibitors.
Author contributions: FL and MLG performed the experiments. FL wrote the paper. JB and YFW analyzed, organized the data and contributed to cell culture procedure. XQL conceived, designed the study, and obtained the authors approved the final version of the paper.
Conflicts of interest: There are no conflicts of interest regarding financial interests, authorship, and copyright.
Financial support: This study was supported by the National Natural Science Foundation of China, No. . The funding body played no role in the study design, in the collection, analysis and interpretation of data, in the writing of the paper, and in the decision to submit the paper for publication.
Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement: Datasets analyzed during the current study are available from the corresponding author on reasonable request.
Plagiarism check: Checked twice by iThenticate.
Peer review: Externally peer reviewed.
Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
Open peer reviewer: Hiroyuki Tanaka, Osaka University of Graduate School of Medicine, Japan.
Additional file: Open peer review report 1.
Akbik F, Cafferty WB, Strittmatter SM (2012) Myelin associated inhibitors:a link between injury-induced and experience-dependent plasticity. Exp Neurol 235:43-52.
文章来源:《新商务周刊》 网址: http://www.xswzkzzs.cn/qikandaodu/2020/1021/526.html