title: The smooth muscle microRNA miR-145 regulates gut epithelial development via a paracrine mechanism.
abstract: MicroRNAs are potent modulators of cellular differentiation. miR-145 is expressed in, and promotes the differentiation of vascular and visceral smooth muscle cells (SMCs). Interestingly, we have observed that miR-145 also promotes differentiation of the gut epithelium in the developing zebrafish, a cell type where it is not expressed. Here we identify that a paracrine pathway involving the morphogens Sonic hedgehog (Shh) in epithelium and bone morphogenic protein 4 (Bmp4) in SMCs is modulated by miR-145. We show that expression of miR-145 in visceral SMCs normally represses the expression of the morphogen bmp4, as loss of miR-145 leads to upregulation of bmp4 in SMCs. We show that bmp4 in turn controls expression of Shh in the visceral epithelium. Conversely, in miR-145 morphants where bmp4 expression is increased, expression of sonic hedgehog a (shha) is strongly increased in gut epithelium. We show that expression of bmp4 is modulated by the miR-145 direct target gata6 but not a second potential direct target, klf5a. Thus although miR-145 is a tissue-restricted microRNA, it plays an essential role in promoting the patterning of both gut layers during gut development via a paracrine mechanism.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Childs
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004064:Digestive System / Q000196:embryology / Q000378:metabolism; D050980:GATA Transcription Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D060172:Morpholinos / Q000235:genetics; D009130:Muscle, Smooth / Q000196:embryology / Q000378:metabolism; D032390:Myoblasts, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D019899:Paracrine Communication; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D050980:GATA Transcription Factors; C525956:Gata6 protein, zebrafish; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C544858:Mirn145 microRNA, zebrafish; D060172:Morpholinos; C524053:Shha protein, zebrafish; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish