title: Transgenic Expression of miR-222 Disrupts Intestinal Epithelial Regeneration by Targeting Multiple Genes Including Frizzled-7.
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 diseasesin 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 theFzd7messenger ribonucleic acid (mRNA) as a novel target of miR-222 and found that [miR-222/Fzd7mRNA] association repressedFzd7mRNA translation. These results implicate miR-222 as a negative regulator of normal intestinal epithelial regeneration and protection by downregulating expression of multiple genes including theFzd7. Our findings also suggest a novel role of increased miR-222 in the pathogenesis of mucosal growth inhibition, delayed healing and barrier dysfunction.
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Hee Kyoung
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Jaladanki N
authors.initials: JN
authors.lastname: Rao
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Turner
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
authors.affiliation: Laboratory of Genetics, National Institute on Aging (NIA)-Intramural Research Program (IRP), National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Baltimore Veterans Affairs Medical Center, Baltimore, Maryland, United States of America.|Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang