RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway.
Bottom Line: 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.
Affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;Show MeSH
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Mentions: Generally, IE-HuR−/− mice looked normal; there were no significant differences in body weight (Figure 2A), gastrointestinal gross morphology (Figure 2B), reproduction, and general appearances between IE-HuR−/− mice and littermate controls. Of interest, IE-HuR−/− mice exhibited significant mucosal atrophy in the small intestine, as indicated by a decrease in the lengths of villi and crypts (Figure 2, C and D). The proliferating crypt cell population, marked by bromodeoxyuridine (BrdU; S phase), decreased remarkably in the small intestine of HuR−/− mice compared with those from littermates (Figure 2E). Accordingly, the levels of cell proliferation marker proteins proliferating cell nuclear antigen (PCNA) and Ki67 were also decreased in the small intestinal mucosa of IE-HuR−/− mice (Figure 2F). Moreover, the loss of HuR in IECs inhibited the regenerative potential of crypt progenitors, since S-phase descendants in the villous regions decreased significantly in IE-HuR−/− mice compared with those observed in control littermates after exposure to irradiation (Figure 3, A and B). Consistently, the villus/crypt ratio in IE-HuR−/− mice also decreased when measured 10 h after irradiation (Figure 3C). We also examined changes in colonic mucosal growth in IE-HuR−/− mice and found that epithelium-specific HuR deletion did not alter mucosal growth in the colon. There were no significant decreases in the lengths of villi and crypts and BrdU-labeled cell proliferation in IE-HuR−/− mice compared with littermate controls (unpublished data). In addition, specific HuR deletion in IECs did not affect lineage differentiation in the intestine (Supplemental Figure S2, A and B), gut permeability (Supplemental Figure S2C), or crypt number per tissue area (Supplemental Figure S2D). These results indicate that conditional HuR deletion in IECs results in small intestinal mucosal atrophy but does not alter colonic mucosal growth.
Affiliation: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Veterans Affairs Medical Center, Baltimore, MD 21201;