RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway

  • Lan Liu
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Eleni Christodoulou-Vafeiadou
    Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece;
  • Jaladanki N. Rao
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Tongtong Zou
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Lan Xiao
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Hee Kyoung Chung
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Hong Yang
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
  • Myriam Gorospe
    Laboratory of Genetics, National Institute on Aging–Intramural Research Program, National Institutes of Health, Baltimore, MD 21224
  • Dimitris Kontoyiannis
    Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece;
  • Jian-Ying Wang
    Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201

説明

<jats:p> Inhibition of growth of the intestinal epithelium, a rapidly self-renewing tissue, is commonly found in various critical disorders. The RNA-binding protein HuR is highly expressed in the gut mucosa and modulates the stability and translation of target mRNAs, but its exact biological function in the intestinal epithelium remains unclear. Here, we investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells caused significant mucosal atrophy in the small intestine, as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. In addition, the HuR-deficient intestinal epithelium also displayed decreased regenerative potential of crypt progenitors after exposure to irradiation. HuR deficiency decreased expression of the Wnt coreceptor LDL receptor–related protein 6 (LRP6) in the mucosal tissues. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3′-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for normal mucosal growth in the small intestine by altering Wnt signals through up-regulation of LRP6 expression and highlight a novel role of HuR deficiency in the pathogenesis of intestinal mucosal atrophy under pathological conditions. </jats:p>

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