Genome expression profiling predicts the molecular mechanism of peripheral myelination

Wu,Xiaoming

doi:10.3892/ijmm.2017.3348

Genome expression profiling predicts the molecular mechanism of peripheral myelination

Authors:
- Xiaoming Wu
View Affiliations

Affiliations: Department of Radiology, Jinhua People's Hospital, Jinhua, Zhejiang 321000, P.R. China
Published online on: December 22, 2017 https://doi.org/10.3892/ijmm.2017.3348
Pages: 1500-1508
Copyright: © Wu . This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to explore the molecular mechanism of myelination in the peripheral nervous system (PNS) based on genome expression profiles. Microarray data (GSE60345) was acquired from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were integrated and subsequently subjected to pathway and term enrichment analysis. A protein‑protein interaction network was constructed and the top 200 DEGs according to their degree value were further subjected to pathway enrichment analysis. A microRNA (miR)‑target gene regulatory network was constructed to explore the role of miRs associated with PNS myelination. A total of 783 upregulated genes and 307 downregulated genes were identified. The upregulated DEGs were significantly enriched in the biological function of complement and coagulation cascades, cytokine‑cytokine receptor interactions and cell adhesion molecules. Pathways significantly enriched by the downregulated DEGs included the cell cycle, oocyte meiosis and the p53 signaling pathway. In addition, the upregulated DEGs among the top 200 DEGs were significantly enriched in natural killer (NK) cell mediated cytotoxicity and the B cell receptor (BCR) signaling pathway, in which Fc γ receptor (FCGR), ras‑related C3 botulinum toxin substrate 2 (RAC2) and 1‑phosphatidylinositol‑4,5‑bisphosphate phosphodiesterase γ‑2 (PLCG2) were involved. miR‑339‑5p, miR‑10a‑5p and miR‑10b‑5p were identified as having a high degree value and may regulate the target genes TOX high mobility group box family member 4 (Tox4), DNA repair protein XRCC2 (Xrcc2) and C5a anaphylatoxin chemotactic receptor C5a2 (C5ar2). NK cell mediated cytotoxicity and the BCR pathway may be involved in peripheral myelination by targeting FCGR, RAC2 and PLCG2. The downregulation of oocyte meiosis, the cell cycle and the cellular tumor antigen p53 signaling pathway suggests decreasing schwann cell proliferation following the initiation of myelination. miR‑339‑5p, miR‑10a‑5p and miR‑10b‑5p may play important roles in PNS myelination by regulating Tox4, Xrcc2 and C5ar2.

View Figures

View References

1	Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J and Shy ME: Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 6:1516–1527. 2000. View Article : Google Scholar
2	Pereira JA, Lebrun-Julien F and Suter U: Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci. 35:123–134. 2012. View Article : Google Scholar
3	Nave KA: Myelination and support of axonal integrity by glia. Nature. 468:244–252. 2010. View Article : Google Scholar : PubMed/NCBI
4	Ritter ST, Jense RJ and Davies JM: Subarachnoid and peripheral nerve block in a patient with Charcot-Marie-Tooth disease. Open J Anesthesiol. 3:44–47. 2013. View Article : Google Scholar
5	Nave KA and Werner HB: Myelination of the nervous system: Mechanisms and functions. Annu Rev Cell Dev Biol. 30:503–533. 2014. View Article : Google Scholar : PubMed/NCBI
6	Birchmeier C and Nave KA: Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia. 56:1491–1497. 2008. View Article : Google Scholar : PubMed/NCBI
7	Taveggia C, Zanazzi G, Petrylak A, Yano H, Rosenbluth J, Einheber S, Xu X, Esper RM, Loeb JA, Shrager P, et al: Neuregulin-1 Type III determines the ensheathment fate of axons. Neuron. 47:681–694. 2005. View Article : Google Scholar : PubMed/NCBI
8	Kao SC, Wu H, Xie J, Chang CP, Ranish JA, Graef IA and Crabtree GR: Calcineurin/NFAT signaling is required for neuregulin-regulated schwann cell differentiation. Science. 323:651–654. 2009. View Article : Google Scholar : PubMed/NCBI
9	Ye H, Jin YK, Dupree J, Tewari A, Melendez-Vasquez C, Svaren J and Casaccia P: Yy1 as a molecular link between neuregulin and transcriptional modulation of peripheral myelination. Nat Neurosci. 13:1472–1480. 2010. View Article : Google Scholar
10	Tawk M, Makoukji J, Belle M, Fonte C, Trousson A, Hawkins T, Li H, Ghandour S, Schumacher M and Massaad C: Wnt/beta-catenin signaling is an essential and direct driver of myelin gene expression and myelinogenesis. J Neurosci. 31:3729–3742. 2011. View Article : Google Scholar : PubMed/NCBI
11	Stendel C, Roos A, Kleine H, Arnaud E, Ozçelik M, Sidiropoulos PN, Zenker J, Schüpfer F, Lehmann U, Sobota RM, et al: SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling. Brain. 133:2462–2474. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yoshimura K and Takeda S: Hedgehog signaling regulates myelination in the peripheral nervous system through primary cilia. Differentiation. 83:S78–S85. 2012. View Article : Google Scholar
13	Obernosterer G, Leuschner PJ, Alenius M and Martinez J: Post-transcriptional regulation of microRNA expression. RNA. 12:1161–1167. 2006. View Article : Google Scholar : PubMed/NCBI
14	Wu D and Murashov AK: Molecular mechanisms of peripheral nerve regeneration: Emerging roles of microRNAs. Front Physiol. 4:552013. View Article : Google Scholar : PubMed/NCBI
15	Yi S, Yuan Y, Chen Q, Wang X, Gong L, Liu J, Gu X and Li S: Regulation of Schwann cell proliferation and migration by miR-1 targeting brain-derived neurotrophic factor after peripheral nerve injury. Sci Rep. 6:291212016. View Article : Google Scholar : PubMed/NCBI
16	Adilakshmi T, Sudol I and Tapinos N: Combinatorial action of miRNAs regulates transcriptional and post-transcriptional gene silencing following in vivo PNS injury. PLoS One. 7:e396742012. View Article : Google Scholar : PubMed/NCBI
17	Yu B, Zhou S, Wang Y, Qian T, Ding G, Ding F and Gu X: miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury. J Cell Sci. 125:2675–2683. 2012. View Article : Google Scholar : PubMed/NCBI
18	Zhou S, Gao R, Hu W, Qian T, Wang N, Ding G, Ding F, Yu B and Gu X: MiR-9 inhibits Schwann cell migration by targeting Cthrc1 following sciatic nerve injury. J Cell Sci. 127:967–976. 2014. View Article : Google Scholar : PubMed/NCBI
19	Verrier JD, Lau P, Hudson L, Murashov AK, Renne R and Notterpek L: Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a. Glia. 57:1265–1279. 2009. View Article : Google Scholar : PubMed/NCBI
20	Yun B, Anderegg A, Menichella D, Wrabetz L, Feltri ML and Awatramani R: MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci. 30:7722–7728. 2010. View Article : Google Scholar : PubMed/NCBI
21	Gökbuget D, Pereira JA, Bachofner S, Marchais A, Ciaudo C, Stoffel M, Schulte JH and Suter U: The Lin28/let-7 axis is critical for myelination in the peripheral nervous system. Nat Commun. 6:85842015. View Article : Google Scholar : PubMed/NCBI
22	Kangas SM, Ohlmeier S, Sormunen R, Jouhilahti EM, Peltonen S, Peltonen J and Heape AM: An approach to comprehensive genome and proteome expression analyses in Schwann cells and neurons during peripheral nerve myelin formation. J Neurochem. 138:830–844. 2016. View Article : Google Scholar : PubMed/NCBI
23	Verrier JD, Lau P, Hudson L, Murashov AK, Renne R and Notterpek L: Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a. Glia. 57:1265–1279. 2009. View Article : Google Scholar : PubMed/NCBI
24	Dugas JC, Cuellar TL, Scholze A, Ason B, Ibrahim A, Emery B, Zamanian JL, Foo LC, Mcmanus MT and Barres BA: Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 65:597–611. 2010. View Article : Google Scholar : PubMed/NCBI
25	Barrett T, Suzek TO, Troup DB, Wilhite SE, Ngau WC, Ledoux P, Rudnev D, Lash AE, Fujibuchi W and Edgar R: NCBI GEO: Mining millions of expression profiles-database and tools. Nucleic Acids Res. 33:D562–D566. 2005. View Article : Google Scholar
26	Smyth GK: Limma: Linear models for microarray data. bioinformatics and computational biology solutions using R and bioconductor. Gentleman R, Carey V, Dudoit S, Irizarry R and Huber W: Springer; New York: pp. 397–420. 2005, View Article : Google Scholar
27	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
28	Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P, et al: The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 39:D561–D568. 2011. View Article : Google Scholar :
29	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
30	Dweep H and Gretz N: miRWalk2.0: A comprehensive atlas of microRNA-target interactions. Nat Methods. 12:6972015. View Article : Google Scholar : PubMed/NCBI
31	Saporta MA and Shy ME: Inherited peripheral neuropathies. Continuum. 17:294–315. 2013.
32	Ratelade J, Zhang H, Saadoun S, Bennett JL, Papadopoulos MC and Verkman AS: Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol. 123:861–872. 2012. View Article : Google Scholar : PubMed/NCBI
33	Takahashi K, Aranami T, Endoh M, Miyake S and Yamamura T: The regulatory role of natural killer cells in multiple sclerosis. Brain. 127:1917–1927. 2004. View Article : Google Scholar : PubMed/NCBI
34	Suzuki H, Matsuda S, Terauchi Y, Fujiwara M, Ohteki T, Asano T, Behrens TW, Kouro T, Takatsu K, Kadowaki T and Koyasu S: PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction. Nat Immunol. 4:280–286. 2003. View Article : Google Scholar : PubMed/NCBI
35	Vedeler CA and Fitzpatrick-Kløve L: Receptors for immunoglobulin G demonstrated on human peripheral nerve fibres by electron microscopy. Neurosci Lett. 115:167–170. 1990. View Article : Google Scholar : PubMed/NCBI
36	Kaida K: Antibodies to glycoconjugates in autoimmune neuropathies. Clin Experimental Neuroimmunol. 6:387–394. 2015. View Article : Google Scholar
37	Yang FC, Kapur R, King AJ, Tao W, Kim C, Borneo J, Breese R, Marshall M, Dinauer MC and Williams DA: Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity. 12:557–568. 2000. View Article : Google Scholar : PubMed/NCBI
38	Cotter L, Ozçelik M, Jacob C, Pereira JA, Locher V, Baumann R, Relvas JB, Suter U and Tricaud N: Dlg1-PTEN interaction regulates myelin thickness to prevent damaging peripheral nerve overmyelination. Science. 328:1415–1418. 2010. View Article : Google Scholar : PubMed/NCBI
39	Levaillant CJ, Sharma A, Muhling J, Wheeler LP, Cozens GS, Hellström M, Rodger J and Harvey AR: Significant changes in endogenous retinal gene expression assessed 1 year after a single intraocular injection of AAV-CNTF or AAV-BDNF. Mol Ther Methods Clin Dev. 3:160782016. View Article : Google Scholar : PubMed/NCBI
40	Wan L, Xia R and Ding W: Short-term low-frequency electrical stimulation enhanced remyelination of injured peripheral nerves by inducing the promyelination effect of brain-derived neurotrophic factor on Schwann cell polarization. J Neurosci Res. 88:2578–2587. 2010.PubMed/NCBI
41	Mikule K, Delaval B, Kaldis P, Jurcyzk A, Hergert P and Doxsey S: Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest. Nat Cell Biol. 9:160–170. 2007. View Article : Google Scholar : PubMed/NCBI
42	Jessen KR and Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 6:671–682. 2005. View Article : Google Scholar : PubMed/NCBI
43	Long JM, Ray B and Lahiri DK: MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem. 289:5184–5198. 2014. View Article : Google Scholar
44	Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C and Haass C: Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 314:664–666. 2006. View Article : Google Scholar : PubMed/NCBI
45	Zhang Y, Wei G, Di Z and Zhao Q: miR-339-5p inhibits alcohol-induced brain inflammation through regulating NF-κB pathway. Biochem Biophys Res Commun. 452:450–456. 2014. View Article : Google Scholar : PubMed/NCBI
46	Jansson MD, Damas ND, Lees M, Jacobsen A and Lund AH: miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2. Oncogene. 34:1908–1918. 2014. View Article : Google Scholar : PubMed/NCBI
47	Müller S: In silico analysis of regulatory networks underlines the role of miR-10b-5p and its target BDNF in huntington's disease. Transl Neurodegener. 3:172014. View Article : Google Scholar : PubMed/NCBI
48	Prins SA, Przybycien-Szymanska MM, Rao YS and Pak TR: Long-term effects of peripubertal binge EtOH exposure on hippocampal microRNA expression in the rat. PLoS One. 9:e831662014. View Article : Google Scholar : PubMed/NCBI
49	Tolwani RJ, Cosgaya JM, Varma S, Jacob R, Kuo LE and Shooter EM: BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J Neurosci Res. 77:662–669. 2004. View Article : Google Scholar : PubMed/NCBI
50	Havre PA, Rice M, Ramos R and Kmiec EB: HsRec2/Rad51L1, a protein influencing cell cycle progression, has protein kinase activity. Exp Cell Res. 254:33–44. 2000. View Article : Google Scholar : PubMed/NCBI
51	Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB and Talbot WS: A G protein-coupled receptor is essential for schwann cells to initiate myelination. Science. 325:1402–1405. 2009. View Article : Google Scholar : PubMed/NCBI