MicroRNAs Control Intestinal Epithelial Differentiation, Architecture, and Barrier Function

Abstract

Background and Aims While the importance of miRNA for the development and maintenance of several tissues is well established, its role in the intestine is unknown. Our aims were to determine the entire miRNA expression profile of the mammalian small intestine in a quantitative manner and to determine the contribution of miRNAs to intestinal development and homeostasis using genetic means. Methods We determined the complete miRNA transcriptome of the mouse intestinal epithelium using ultra-high throughput sequencing. We employed gene ablation of Dicer1 to generate mice deficient for all miRNAs in the mouse intestine. Results miRNA abundance varies over a large dynamic range in the mammalian small intestine, from one read per million to 250,000. Of the 453 miRNA families identified, mmu-miR-192 and mmu-let-7 are the most highly expressed. Morphologically, the epithelium of Dicer1loxP/loxP; Villin-Cre mutants mice is disorganized in both the small and large intestine, with a four-fold decrease in goblet cells in the colon and a dramatic increase in apoptosis in the crypts of both the large and small intestine. Furthermore, intestinal barrier function is dependent on the presence of miRNAs, and consequently Dicer1 deficient mice display intestinal inflammation with lymphocyte and neutrophil infiltration. Conclusion We have identified all intestinal miRNAs and shown using gene ablation of Dicer1 that miRNAs play a vital role in the differentiation and function of the intestinal epithelium.

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

“…Disruption of the intestinal barrier has been shown to be an important pathogenic mechanism contributing to the development of intestinal inflammation [22,23] . McKenna et al [24] reported that miRNAs are important for maintaining the function of intestinal barriers. miR21, which is overexpressed in chronic UC, induces the degradation of Ras homolog gene family member (Rho)B mRNA and leads to an increase in intestinal epithelial permeability due to the loss of TJ proteins and ultrastructural changes [25] .…”

miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis

“…As master regulators of post-transcription in cells, these regulatory miRNAs are involved in key functions in many physiological networks [21][22][23] , and differentially expression miRNAs have been implicated in the pathogenesis of diverse gastrointestinal disorders, such as cancer and inflammatory diseases [24,25] . In facts, loss of intestinal miRNAs in mouse models has been shown to impair differentiation of intestinal cells and epithelial barrier function, resulting in acute inflammation [23] .…”

Regulation of mouse stomach development and Barx1 expression by specific microRNAs

“…Other studies implicate selected miRNAs in the development of vertebrate limbs (Hornstein et al, 2005), muscle (Chen et al, 2006;Cordes et al, 2009), heart (Zhao et al, 2007), neurons (Makeyev et al, 2007), blood Thai et al, 2007), retina (Decembrini et al, 2009) and intestine (Zeng et al, 2009). One recent study profiled miRNAs expressed in the mouse intestine and showed, through tissue-specific loss of all miRNAs, that they are necessary for epithelial barrier function (McKenna et al, 2010). More than 1000 miRNAs have been identified and some are known to sharpen spatial or temporal borders of gene expression (Stefani and Slack, 2008), but few miRNAs have well-established functions and defined target genes in tissue development and organogenesis.…”