Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Sequencing data were uploaded to NCBI database (Accession Number PRJNA394957; SRP113121).

References

  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. https://doi.org/10.1016/j.cell.2018.01.029

    Article  CAS  PubMed  Google Scholar 

  2. Latchman DS (1997) Transcription factors: an overview. Int J Biochem Cell Biol 29(12):1305–1312

    Article  CAS  Google Scholar 

  3. Ptashne M, Gann A (1997) Transcriptional activation by recruitment. Nature 386(6625):569–577. https://doi.org/10.1038/386569a0

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nrg2538

    Article  CAS  PubMed  Google Scholar 

  5. Lambert M, Jambon S, Depauw S, David-Cordonnier MH (2018) Targeting transcription factors for cancer treatment. Molecules. https://doi.org/10.3390/molecules23061479

    Article  PubMed  PubMed Central  Google Scholar 

  6. Takei H, Kobayashi SS (2019) Targeting transcription factors in acute myeloid leukemia. Int J Hematol 109(1):28–34. https://doi.org/10.1007/s12185-018-2488-1

    Article  CAS  PubMed  Google Scholar 

  7. Coomans de Brachene A, Demoulin JB (2016) FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci 73(6):1159–1172. https://doi.org/10.1007/s00018-015-2112-y

    Article  CAS  PubMed  Google Scholar 

  8. Patodia S, Raivich G (2012) Role of transcription factors in peripheral nerve regeneration. Front Mol Neurosci 5:8. https://doi.org/10.3389/fnmol.2012.00008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.4103/1673-5374.237183

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/srep16888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):116–122

    Article  CAS  Google Scholar 

  12. Wu D, Murashov AK (2013) Molecular mechanisms of peripheral nerve regeneration: emerging roles of microRNAs. Front Physiol 4:55. https://doi.org/10.3389/fphys.2013.00055

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.pneurobio.2010.11.002

    Article  CAS  PubMed  Google Scholar 

  14. Chen ZL, Yu WM, Strickland S (2007) Peripheral regeneration. Annu Rev Neurosci 30:209–233. https://doi.org/10.1146/annurev.neuro.30.051606.094337

    Article  CAS  Google Scholar 

  15. Navarro X, Vivo M, Valero-Cabre A (2007) Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 82(4):163–201. https://doi.org/10.1016/j.pneurobio.2007.06.005

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0143491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1186/s13041-018-0421-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bosse F (2012) Extrinsic cellular and molecular mediators of peripheral axonal regeneration. Cell Tissue Res 349(1):5–14. https://doi.org/10.1007/s00441-012-1389-5

    Article  CAS  PubMed  Google Scholar 

  19. Wong KM, Babetto E, Beirowski B (2017) Axon degeneration: make the Schwann cell great again. Neural Regen Res 12(4):518–524. https://doi.org/10.4103/1673-5374.205000

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oliveros JC (2007) VENNY. An interactive tool for comparing lists with Venn Diagrams

  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. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1002/mus.24082

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3389/fncel.2017.00323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s11427-011-4213-7

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M405025200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1074/jbc.M208144200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M110850200

    Article  CAS  PubMed  Google Scholar 

  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):1571–1575

    Article  CAS  Google Scholar 

  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):1508–1519

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M208924200

    Article  CAS  PubMed  Google Scholar 

  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):363–372

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2559.2006.02492.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1042/BSR20181928

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.yexcr.2009.08.008

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.biocel.2013.04.024

    Article  CAS  PubMed  Google Scholar 

  36. Scott CC, Vossio S, Rougemont J, Gruenberg J (2018) TFAP2 transcription factors are regulators of lipid droplet biogenesis. Elife. https://doi.org/10.7554/eLife.36330

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

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].

Author information

Author notes

  1. Fuchao Zhang and Xiaokun Gu have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu, China

    Fuchao Zhang, Xiaokun Gu, Sheng Yi & Hui Xu

  2. Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

    Xiaokun Gu

Authors
  1. Fuchao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaokun Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Sheng Yi or Hui Xu.

Ethics declarations

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

List 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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, F., Gu, X., Yi, S. et al. Dysregulated Transcription Factor TFAP2A After Peripheral Nerve Injury Modulated Schwann Cell Phenotype. Neurochem Res 44, 2776–2785 (2019). https://doi.org/10.1007/s11064-019-02898-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02898-y

Keywords

Search

Navigation