Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing



Post-transcriptional switches are flexible effectors of dynamic changes in gene expression1. Here we report a new post-transcriptional switch that dictates the spatiotemporal and mutually exclusive expression of two alternative gene products from a single transcript. Expression of primate-specific exonic microRNA-198 (miR-198)2, located in the 3′-untranslated region of follistatin-like 1 (FSTL1)3 messenger RNA, switches to expression of the linked open reading frame of FSTL1 upon wounding in a human ex vivo organ culture system. We show that binding of a KH-type splicing regulatory protein (KSRP, also known as KHSRP) to the primary transcript determines the fate of the transcript and is essential for the processing of miR-198: transforming growth factor-β signalling switches off miR-198 expression by downregulating KSRP, and promotes FSTL1 protein expression. We also show that FSTL1 expression promotes keratinocyte migration, whereas miR-198 expression has the opposite effect by targeting and inhibiting DIAPH1, PLAU and LAMC2. A clear inverse correlation between the expression pattern of FSTL1 (pro-migratory) and miR-198 (anti-migratory) highlights the importance of this regulatory switch in controlling context-specific gene expression to orchestrate wound re-epithelialization. The deleterious effect of failure of this switch is apparent in non-healing chronic diabetic ulcers, in which expression of miR-198 persists, FSTL1 is absent, and keratinocyte migration, re-epithelialization and wound healing all fail to occur.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Expression of an exonic miRNA or linked open reading frame in context-specific physiological states.
Figure 2: The regulatory switch is impaired in chronic wounds.
Figure 3: KSRP and TGF-β1 regulate the choice between expression of miR-198 or FSTL1.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE37967 and GSE41615.


  1. Anderson, P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nature Rev. Immunol. 10, 24–35 (2010)

    CAS  Article  Google Scholar 

  2. Hinske, L. C., Galante, P. A., Kuo, W. P. & Ohno-Machado, L. A potential role for intragenic miRNAs on their hosts’ interactome. BMC Genomics 11, 533 (2010)

    Article  Google Scholar 

  3. Shibanuma, M., Mashimo, J., Mita, A., Kuroki, T. & Nose, K. Cloning from a mouse osteoblastic cell line of a set of transforming-growth-factor-β1-regulated genes, one of which seems to encode a follistatin-related polypeptide. Eur. J. Biochem. 217, 13–19 (1993)

    CAS  Article  Google Scholar 

  4. Gurtner, G. C., Werner, S., Barrandon, Y. & Longaker, M. T. Wound repair and regeneration. Nature 453, 314–321 (2008)

    ADS  CAS  Article  Google Scholar 

  5. Blakytny, R. & Jude, E. The molecular biology of chronic wounds and delayed healing in diabetes. Diabet. Med. 23, 594–608 (2006)

    CAS  Article  Google Scholar 

  6. Banerjee, J., Chan, Y. C. & Sen, C. K. MicroRNAs in skin and wound healing. Physiol. Genomics 43, 543–556 (2011)

    CAS  Article  Google Scholar 

  7. Tan, S., Li, R., Ding, K., Lobie, P. E. & Zhu, T. miR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. FEBS Lett. 585, 2229–2234 (2011)

    CAS  Article  Google Scholar 

  8. Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957–1966 (2004)

    CAS  Article  Google Scholar 

  9. Hambrock, H. O. et al. Structural characterization of TSC-36/Flik: analysis of two charge isoforms. J. Biol. Chem. 279, 11727–11735 (2004)

    CAS  Article  Google Scholar 

  10. Kroeze, K. L. et al. Autocrine regulation of re-epithelialization after wounding by chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3. J. Invest. Dermatol. 132, 216–225 (2012)

    CAS  Article  Google Scholar 

  11. He, Y., Esser, P., Heinemann, A., Bruckner-Tuderman, L. & Has, C. Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification. Am. J. Pathol. 178, 975–982 (2011)

    CAS  Article  Google Scholar 

  12. Freedberg, I. M., Tomic-Canic, M., Komine, M. & Blumenberg, M. Keratins and the keratinocyte activation cycle. J. Invest. Dermatol. 116, 633–640 (2001)

    CAS  Article  Google Scholar 

  13. Lund, L. R. et al. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J. 25, 2686–2697 (2006)

    CAS  Article  Google Scholar 

  14. Brandt, D. T. et al. Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J. Cell Biol. 178, 193–200 (2007)

    CAS  Article  Google Scholar 

  15. Frank, D. E. & Carter, W. G. Laminin 5 deposition regulates keratinocyte polarization and persistent migration. J. Cell Sci. 117, 1351–1363 (2004)

    CAS  Article  Google Scholar 

  16. Trabucchi, M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459, 1010–1014 (2009)

    ADS  CAS  Article  Google Scholar 

  17. Wang, B. et al. TGFβ-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 29, 1787–1797 (2010)

    CAS  Article  Google Scholar 

  18. Jude, E. B., Blakytny, R., Bulmer, J., Boulton, A. J. & Ferguson, M. W. Transforming growth factor-beta 1, 2, 3 and receptor type I and II in diabetic foot ulcers. Diabet. Med. 19, 440–447 (2002)

    CAS  Article  Google Scholar 

  19. Pastar, I. et al. Attenuation of the transforming growth factor β-signaling pathway in chronic venous ulcers. Mol. Med. 16, 92–101 (2010)

    CAS  Article  Google Scholar 

  20. Usui, M. L. et al. Morphological evidence for the role of suprabasal keratinocytes in wound reepithelialization. Wound Repair Regen. 13, 468–479 (2005)

    Article  Google Scholar 

  21. Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003)

    ADS  CAS  Article  Google Scholar 

  22. Daniel, R. J. & Groves, R. W. Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator. J. Invest. Dermatol. 119, 1304–1309 (2002)

    CAS  Article  Google Scholar 

  23. Marutsuka, K., Woodcock-Mitchell, J., Sakamoto, T., Sobel, B. E. & Fujii, S. Pathogenetic implications of hyaluronan-induced modification of vascular smooth muscle cell fibrinolysis in diabetes. Coron. Artery Dis. 9, 177–184 (1998)

    CAS  Article  Google Scholar 

  24. Zorio, E. et al. Fibrinolysis: the key to new pathogenetic mechanisms. Curr. Med. Chem. 15, 923–929 (2008)

    CAS  Article  Google Scholar 

  25. Usui, M. L., Mansbridge, J. N., Carter, W. G., Fujita, M. & Olerud, J. E. Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds. J. Histochem. Cytochem. 56, 687–696 (2008)

    CAS  Article  Google Scholar 

  26. Stojadinovic, O. et al. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am. J. Pathol. 167, 59–69 (2005)

    CAS  Article  Google Scholar 

  27. Jeffcoate, W. J. & Harding, K. G. Diabetic foot ulcers. Lancet 361, 1545–1551 (2003)

    Article  Google Scholar 

  28. Brem, H. & Tomic-Canic, M. Cellular and molecular basis of wound healing in diabetes. J. Clin. Invest. 117, 1219–1222 (2007)

    CAS  Article  Google Scholar 

Download references


This work was supported by an A*STAR Investigatorship award to P.S., the Biomedical Research Council of Singapore and the Skin Biology Cluster Platform, A*STAR. We thank T. Kamala, S. Nama, M. Hisyam and C. Vaz for experimental support and B. Knowles for critical reading of the manuscript.

Author information

Authors and Affiliations



G.M.S. and J.E.A.C. performed most of the experiments; F.E.G. and D.P.L. helped with immunohistochemistry; K.L., T.C.L. and S.S. assisted in procurement of patient samples; V.T. helped in microarray data analysis; E.B.L. assisted in experimental design and contributed to writing the manuscript; and P.S. designed experiments, supervised this work and wrote the manuscript.

Corresponding author

Correspondence to Prabha Sampath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-17 and lists of primers a-c. (PDF 1176 kb)

Live cell imaging of scratch wound assay in keratinocytes over-expressing miR-198

Keratinocytes over-expressing miR-198 were plated as a monolayer and subjected to scratch wound assay. Video represents time lapse imaging performed every one hour after wounding for a period of 48 hours. (MOV 4840 kb)

Live cell imaging of scratch wound assay in keratinocytes over-expressing control miRNA

Keratinocytes over-expressing control miRNA were plated as a monolayer and subjected to scratch wound assay. Video represents time lapse imaging performed every one hour after wounding for a period of 48 hours. (MOV 4832 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sundaram, G., Common, J., Gopal, F. et al. ‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing. Nature 495, 103–106 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing