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Molecular Medicine

, Volume 21, Issue 1, pp 676–687 | Cite as

Transgenic Expression of miR-222 Disrupts Intestinal Epithelial Regeneration by Targeting Multiple Genes Including Frizzled-7

  • Hee Kyoung Chung
  • Yu Chen
  • Jaladanki N. Rao
  • Lan Liu
  • Lan Xiao
  • Douglas J. Turner
  • Peixin Yang
  • Myriam Gorospe
  • Jian-Ying Wang
Research Article

Abstract

Defects in intestinal epithelial integrity occur commonly in various pathologies. miR-222 is implicated in many aspects of cellular function and plays an important role in several diseases, but its exact biological function in the intestinal epithelium is underexplored. We generated mice with intestinal epithelial tissue-specific overexpression of miR-222 to investigate the function of miR-222 in intestinal physiology and diseases in vivo. Transgenic expression of miR-222 inhibited mucosal growth and increased susceptibility to apoptosis in the small intestine, thus leading to mucosal atrophy. The miR-222-elevated intestinal epithelium was vulnerable to pathological stress, since local overexpression of miR-222 not only delayed mucosal repair after ischemia/reperfusion-induced injury, but also exacerbated gut barrier dysfunction induced by exposure to cecal ligation and puncture. miR-222 overexpression also decreased expression of the Wnt receptor Frizzled-7 (FZD7), cyclin-dependent kinase 4 and tight junctions in the mucosal tissue. Mechanistically, we identified the Fzd7 messenger ribonucleic acid (mRNA) as a novel target of miR-222 and found that [miR-222/Fzd7 mRNA] association repressed Fzd7 mRNA translation. These results implicate miR-222 as a negative regulator of normal intestinal epithelial regeneration and protection by downregulating expression of multiple genes including the Fzd7. Our findings also suggest a novel role of increased miR-222 in the pathogenesis of mucosal growth inhibition, delayed healing and barrier dysfunction.

Notes

Acknowledgments

Funding was provided by Merit Review Awards (to JY Wang, DJ Turner and JN Rao) from the U.S. Department of Veterans Affairs; grants from the National Institutes of Health (DK57819, DK61972 and DK68491 to JY Wang); and the National Institute on Aging-Intramural Research Program (to M Gorospe). JY Wang is a Senior Research Career Scientist, Biomedical Laboratory Research and Development Service, U.S. Department of Veterans Affairs.

Supplementary material

10020_2015_2101676_MOESM1_ESM.pdf (6.8 mb)
Supplementary material, approximately 6.76 MB.

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© The Author(s) 2015

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Authors and Affiliations

  • Hee Kyoung Chung
    • 1
    • 2
  • Yu Chen
    • 1
    • 2
  • Jaladanki N. Rao
    • 1
    • 2
  • Lan Liu
    • 1
    • 2
  • Lan Xiao
    • 1
    • 2
  • Douglas J. Turner
    • 1
    • 2
  • Peixin Yang
    • 3
  • Myriam Gorospe
    • 4
  • Jian-Ying Wang
    • 1
    • 2
    • 5
  1. 1.Cell Biology Group, Department of SurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Baltimore Veterans Affairs Medical Center (112)BaltimoreUSA
  3. 3.Department of Obstetrics, Gynecology, and Reproductive SciencesUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Laboratory of Genetics, National Institute on Aging (NIA)-Intramural Research Program (IRP)National Institutes of HealthBaltimoreUSA
  5. 5.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA

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