title: RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway.
abstract: 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.
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece;
authors.forename: Eleni
authors.initials: E
authors.lastname: Christodoulou-Vafeiadou
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
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, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
authors.forename: Tongtong
authors.initials: T
authors.lastname: Zou
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
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, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece;
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kontoyiannis
authors.affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201 jwang@smail.umaryland.edu.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008817:Mice, Mutant Strains; D051381:Rats; D060449:Wnt Signaling Pathway
chemical_list: D020413:3' Untranslated Regions; D051959:ELAV Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse