Neurochemical Research

, Volume 44, Issue 12, pp 2776–2785 | Cite as

Dysregulated Transcription Factor TFAP2A After Peripheral Nerve Injury Modulated Schwann Cell Phenotype

  • Fuchao Zhang
  • Xiaokun Gu
  • Sheng YiEmail author
  • Hui XuEmail author
Original Paper


Transcription factors regulate the transcriptions and expressions of numerous target genes and direct a variety of physiological and pathological activities. To obtain a better understanding of the involvement of transcription factors during peripheral nerve repair and regeneration, significantly differentially expressed genes coding for transcription factors in rat sciatic nerves after sciatic nerve crush injury were identified. A total of 9 transcription factor genes, including GBX2, HIF3A, IRF8, LRRC63, SNAI3, SPIB, TBX21, TFAP2A, and ZBTB16 were identified to be commonly differentially expressed at 1, 4, 7, and 14 days after nerve injury. TFAP2A, a gene encoding transcription factor activating enhancer binding protein 2 alpha, was found to be critical in the regulatory network. PCR validation and immunohistochemistry staining of injured rat sciatic nerves showed that TFAP2A expression was significantly up-regulated in the Schwann cells after nerve injury for at least 2 weeks. Schwann cells transfected with TFAP2A-siRNA exhibited elevated proliferation rate and migration ability, suggesting that TFAP2A suppressed Schwann cell proliferation and migration. Collectively, our study provided a global overview of the dynamic changes of transcription factors after sciatic nerve injury, discovered key transcription factors for the regeneration process, and deepened the understanding of the molecular mechanisms underlying peripheral nerve repair and regeneration.


Transcription factor TFAP2A Peripheral nerve injury Schwann cells Proliferation Migration 


Author Contributions

Conceived and designed the experiments: SY HX. Performed the experiments: FZ XG. Analyzed the data: FZ XG SY. Contributed reagents/materials/analysis tools: SY. Wrote the manuscript: SY HX.


This work was supported by the National Natural Science Foundation of China [31700926], and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China [PAPD].

Compliance with Ethical Standards

Ethics Approval and Consent to Participate

All the experimental procedures involving animals were conducted in accordance with Institutional Animal Care guidelines of Nantong University and approved ethically by the Administration Committee of Experimental Animals, Jiangsu, China.

Supplementary material

11064_2019_2898_MOESM1_ESM.xlsx (13 kb)
Table S1List of significantly differentially expressed transcription factors in the sciatic nerves at 1, 4, 7, and 14 days after crush injury. Gene Symbol, relative expression level (Log Ratio), FDR (q-value), gene ID, gene name, and gene localization were labeled. Supplementary material 1 (XLSX 13.0 kb)


  1. 1.
    Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT (2018) The human transcription factors. Cell 172(4):650–665. CrossRefPubMedGoogle Scholar
  2. 2.
    Latchman DS (1997) Transcription factors: an overview. Int J Biochem Cell Biol 29(12):1305–1312CrossRefGoogle Scholar
  3. 3.
    Ptashne M, Gann A (1997) Transcriptional activation by recruitment. Nature 386(6625):569–577. CrossRefPubMedGoogle Scholar
  4. 4.
    Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM (2009) A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10(4):252–263. CrossRefPubMedGoogle Scholar
  5. 5.
    Lambert M, Jambon S, Depauw S, David-Cordonnier MH (2018) Targeting transcription factors for cancer treatment. Molecules. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Takei H, Kobayashi SS (2019) Targeting transcription factors in acute myeloid leukemia. Int J Hematol 109(1):28–34. CrossRefPubMedGoogle Scholar
  7. 7.
    Coomans de Brachene A, Demoulin JB (2016) FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci 73(6):1159–1172. CrossRefPubMedGoogle Scholar
  8. 8.
    Patodia S, Raivich G (2012) Role of transcription factors in peripheral nerve regeneration. Front Mol Neurosci 5:8. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Qin J, Wu JC, Wang QH, Zhou SL, Mao SS, Yao C (2018) Transcription factor networks involved in cell death in the dorsal root ganglia following peripheral nerve injury. Neural Regen Res 13(9):1622–1627. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Li S, Xue C, Yuan Y, Zhang R, Wang Y, Wang Y, Yu B, Liu J, Ding F, Yang Y, Gu X (2015) The transcriptional landscape of dorsal root ganglia after sciatic nerve transection. Sci Rep 5:16888. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Noble J, Munro CA, Prasad VS, Midha R (1998) Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 45(1):116–122CrossRefGoogle Scholar
  12. 12.
    Wu D, Murashov AK (2013) Molecular mechanisms of peripheral nerve regeneration: emerging roles of microRNAs. Front Physiol 4:55. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gu X, Ding F, Yang Y, Liu J (2011) Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration. Prog Neurobiol 93(2):204–230. CrossRefPubMedGoogle Scholar
  14. 14.
    Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233. CrossRefGoogle Scholar
  15. 15.
    Navarro X, Vivo M, Valero-Cabre A (2007) Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 82(4):163–201. CrossRefPubMedGoogle Scholar
  16. 16.
    Yi S, Zhang H, Gong L, Wu J, Zha G, Zhou S, Gu X, Yu B (2015) Deep sequencing and bioinformatic analysis of lesioned sciatic nerves after crush injury. PLoS ONE 10(12):e0143491. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Qian T, Fan C, Liu Q, Yi S (2018) Systemic functional enrichment and ceRNA network identification following peripheral nerve injury. Mol Brain 11(1):73. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Bosse F (2012) Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res 349(1):5–14. CrossRefPubMedGoogle Scholar
  19. 19.
    Wong KM, Babetto E, Beirowski B (2017) Axon degeneration: make the Schwann cell great again. Neural Regen Res 12(4):518–524. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Oliveros JC (2007) VENNY. An interactive tool for comparing lists with Venn DiagramsGoogle Scholar
  21. 21.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. CrossRefGoogle Scholar
  22. 22.
    Li M, Zhang P, Guo W, Li H, Gu X, Yao D (2014) Protein expression profiling during wallerian degeneration after rat sciatic nerve injury. Muscle Nerve 50(1):73–78. CrossRefPubMedGoogle Scholar
  23. 23.
    Wang H, Zhu H, Guo Q, Qian T, Zhang P, Li S, Xue C, Gu X (2017) Overlapping mechanisms of peripheral nerve regeneration and angiogenesis following sciatic nerve transection. Front Cell Neurosci 11:323. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Li S, Yu B, Wang Y, Yao D, Zhang Z, Gu X (2011) Identification and functional annotation of novel microRNAs in the proximal sciatic nerve after sciatic nerve transection. Sci China Life Sci 54(9):806–812. CrossRefPubMedGoogle Scholar
  25. 25.
    Li Q, Dashwood RH (2004) Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells. J Biol Chem 279(44):45669–45675. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Braganca J, Eloranta JJ, Bamforth SD, Ibbitt JC, Hurst HC, Bhattacharya S (2003) Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. J Biol Chem 278(18):16021–16029. CrossRefPubMedGoogle Scholar
  27. 27.
    Braganca J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S (2002) Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2. J Biol Chem 277(10):8559–8565. CrossRefPubMedGoogle Scholar
  28. 28.
    Campillos M, Garcia MA, Valdivieso F, Vazquez J (2003) Transcriptional activation by AP-2alpha is modulated by the oncogene DEK. Nucleic Acids Res 31(5):1571–1575CrossRefGoogle Scholar
  29. 29.
    Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M (1995) Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J 14(7):1508–1519CrossRefGoogle Scholar
  30. 30.
    McPherson LA, Loktev AV, Weigel RJ (2002) Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53. J Biol Chem 277(47):45028–45033. CrossRefPubMedGoogle Scholar
  31. 31.
    Stewart HJ, Brennan A, Rahman M, Zoidl G, Mitchell PJ, Jessen KR, Mirsky R (2001) Developmental regulation and overexpression of the transcription factor AP-2, a potential regulator of the timing of Schwann cell generation. Eur J Neurosci 14(2):363–372CrossRefGoogle Scholar
  32. 32.
    Harder A, Mautner VF, Friedrich RE, Harder T, Plagemann A, von Deimling A (2006) Transcription factor AP-2 is expressed in human Schwann cell-derived tumours. Histopathology 49(4):441–443. CrossRefPubMedGoogle Scholar
  33. 33.
    Kolat D, Kaluzinska Z, Bednarek AK, Pluciennik E (2019) The biological characteristics of transcription factors AP-2alpha and AP-2gamma and their importance in various types of cancers. Biosci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mitchell DL, DiMario JX (2010) AP-2 alpha suppresses skeletal myoblast proliferation and represses fibroblast growth factor receptor 1 promoter activity. Exp Cell Res 316(2):194–202. CrossRefPubMedGoogle Scholar
  35. 35.
    Ding X, Yang Z, Zhou F, Wang F, Li X, Chen C, Li X, Hu X, Xiang S, Zhang J (2013) Transcription factor AP-2alpha regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression. Int J Biochem Cell Biol 45(8):1647–1656. CrossRefPubMedGoogle Scholar
  36. 36.
    Scott CC, Vossio S, Rougemont J, Gruenberg J (2018) TFAP2 transcription factors are regulators of lipid droplet biogenesis. Elife. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of NeuroregenerationNantong UniversityNantongChina
  2. 2.Department of Hand SurgeryAffiliated Hospital of Nantong UniversityNantongChina

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