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MiR-145 directs intestinal maturation in zebrafish.

ABSTRACT: The rapid specification and differentiation of the embryonic zebrafish gut is essential to provide contractility for the digestion of food. The role of microRNAs in modulating gut epithelial or smooth muscle differentiation is currently not known. Here we show that the microRNA miR-145 is strongly expressed in zebrafish gut smooth muscle and regulates its development. Modulation of miR-145 levels results in gut smooth muscle and epithelium maturation defects. Loss of miR-145 results in defects of smooth muscle function as measured by decreased nitric oxide production but also leads to increased expression of the embryonic smooth muscle markers sm22alpha-b, nm-mhc-b, and smoothelin. Defects in gut epithelial maturation are also present as observed by immature morphology and a complete loss of alkaline phosphatase expression. Loss or gain of miR-145 function phenocopies defects observed with altered gata6 expression and accordingly, we show that miR-145 directly represses gata6, and that gata6 is a major miR-145 target in vitro and in vivo. miR-145 therefore plays a critical role in promoting the maturation of both layers of the gut during development through regulation of gata6.

SUBMITTER: Zeng L

PROVIDER: S-EPMC2764920 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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miR-145 directs intestinal maturation in zebrafish.

Zeng Lei L Carter Alyson D AD Childs Sarah J SJ

Proceedings of the National Academy of Sciences of the United States of America 20091005 42

The rapid specification and differentiation of the embryonic zebrafish gut is essential to provide contractility for the digestion of food. The role of microRNAs in modulating gut epithelial or smooth muscle differentiation is currently not known. Here we show that the microRNA miR-145 is strongly expressed in zebrafish gut smooth muscle and regulates its development. Modulation of miR-145 levels results in gut smooth muscle and epithelium maturation defects. Loss of miR-145 results in defects o ...[more]

PMID: 19805048

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Project description:BackgroundIntestinal barrier impairment plays an essential role in the pathogenesis of Crohn's disease (CD), and claudins (CLDNs) dysfunction contributes to intestinal mucosa injury. SOX9, an important transcription factor, is upregulated in the disease-affected colon of patients with CD; however, its precise role in CD remains largely unknown. Our aim was to explore the interaction between SOX9 and CLDNs, and further elucidate the underlying mechanisms in CD.MethodsSOX9 expression in patients with CD was evaluated using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. The regulatory relationship between SOX9 and CLDNs was analyzed via a dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression, and RNA interference methods. MicroRNAs (miRNAs) involved in the SOX9-CLDN pathway were predicted with bioinformatics analysis, and the upstream molecular mechanism was interpreted using MassARRAY methylation detection.FindingsUpregulated expression of SOX9 in the disease-affected intestine mucosa was identified in both patients with CD and mice challenged with trinitrobenzene sulfonic acid (TNBS). SOX9 negatively regulated the expression of CLDN8, accompanying reduced intestinal permeability. MiR-145-5p downregulation was found in patients with CD and TNBS-induced colitis mice owing to an aberrant miR-145 promoter hypermethylation, which subsequently interfered the SOX9-CLDN8 pathway. MiR-145-5p agomir treatment alleviated TNBS-induced colitis in wild-type mice by inhibiting Sox9 expression and restoring Cldn8 expression, whereas similar findings were not apparent in the Cldn8-/- mice.InterpretationSOX9 mediates the crosstalk between upstream miR-145-5p and downstream CLDN8, and further impairs intestinal mucosal barrier homeostasis in CD. Targeting the miR-145-5p/SOX9/CLDN8 pathway represents a promising therapeutic strategy for CD.FundingThe National Natural Science Foundation of China (#81870374, #81670498, #81630018, #82070538, #8210031148), the Guangdong Science and Technology (#2017A030306021, #2020A1515111087), the Guangzhou Science and Technology Department (#202002030041), and the Fundamental Research Funds for the Central Universities (#19ykzd11).

Dataset Information

MiR-145 directs intestinal maturation in zebrafish.

Publications

miR-145 directs intestinal maturation in zebrafish.

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