miR-145 directs intestinal maturation in zebrafish

Zeng, Lei; Carter, Alyson D.; Childs, Sarah J.

doi:10.1073/pnas.0903693106

Cited by 63 publications

(57 citation statements)

References 41 publications

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“…Previous studies have shown that alterations in miR-145 expression affect overall intestinal maturation (Zeng et al, 2009). To study the role of miR-145 in iSMCs in more detail, we injected low doses of a miR-145 dicer-blocking morpholino, sufficient to significantly reduce mature miR-145 levels without altering endoderm differentiation and overall embryo morphology ( Fig.…”

Section: Foxo1a Is Required For Lpm and Ismc Differentiationmentioning

confidence: 99%

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

et al. 2017

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Intestinal smooth muscle cells (iSMCs) are a crucial component of the adult gastrointestinal tract and support intestinal differentiation, peristalsis and epithelial homeostasis during development. Despite these crucial roles, the origin of iSMCs and the mechanisms responsible for their differentiation and function remain largely unknown in vertebrates. Here, we demonstrate that iSMCs arise from the lateral plate mesoderm (LPM) in a stepwise process. Combining pharmacological and genetic approaches, we show that TGFβ/Alk5 signaling drives the LPM ventral migration and commitment to an iSMC fate. The Alk5-dependent induction of zeb1a and foxo1a is required for this morphogenetic process: zeb1a is responsible for driving LPM migration around the gut, whereas foxo1a regulates LPM predisposition to iSMC differentiation. We further show that TGFβ, zeb1a and foxo1a are tightly linked together by miR-145. In iSMC-committed cells, TGFβ induces the expression of miR-145, which in turn is able to downregulate zeb1a and foxo1a. The absence of miR-145 results in only a slight reduction in the number of iSMCs, which still express mesenchymal genes but fail to contract. Together, our data uncover a cascade of molecular events that govern distinct morphogenetic steps during the emergence and differentiation of vertebrate iSMCs.

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Section: Foxo1a Is Required For Lpm and Ismc Differentiationmentioning

confidence: 99%

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

et al. 2017

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“…Indeed, miRNAs were first identified as regulators of C. elegans developmental chronology (Moss, 2007;Reinhart et al, 2000); moreover, in global analyses, transcripts show higher expression at developmental stages preceding the appearance of their cognate miRNAs and reduced expression as these miRNAs accumulate (Farh et al, 2005;Stark et al, 2005). 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).…”

Section: Introductionmentioning

confidence: 99%

Regulation of mouse stomach development and Barx1 expression by specific microRNAs

et al. 2011

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SUMMARYAlthough microRNAs (miRNAs) are postulated to fine-tune many developmental processes, their relationships with specific targets and tissues remain largely undefined. The mesenchymal transcription factor Barx1 controls spleen and stomach morphogenesis and is required to specify stomach-specific epithelium in adjacent endoderm. Barx1 expression is precisely regulated in space and time, with a sharp drop in stomach levels after epithelial specification. We tested the hypothesis that specific miRNAs mediate this marked decline in Barx1 levels. Depletion of the miRNA-processing enzyme Dicer in cultured stomach mesenchyme and conditional Dicer gene deletion in mice significantly increased Barx1 levels, disrupted stomach and intestine development and caused spleen agenesis. Computational and experimental studies identified miR-7a and miR-203 as candidate miRNAs that regulate Barx1 and are expressed in inverse proportion to it in the fetal mouse stomach. Through specific interactions with cognate sequences in the Barx1 3Ј untranslated region, miR-7a and miR-203 repress Barx1 expression in stomach mesenchymal cells and its function in inducing gastric epithelium. These results indicate that miRNAs are required for proper digestive tract organogenesis and that miR-7a and miR-203 control expression of the stomach homeotic regulator Barx1.

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“…As recent reports have established a role for miR-145 in modulating smooth muscle cell motility and differentiation (Cheng et al, 2009;Cordes et al, 2009;Larsson et al, 2009;Xin et al, 2009;Zeng et al, 2009), we aimed at investigating a potential role for miR-145 in the regulation of breast cancer cell motility in vitro. We demonstrate that restoration of high miR-145 expression levels in a panel of human breast cancer cell lines and an endometrial carcinoma cell line leads to inhibition of JAM-A, a membrane protein involved in cell-cell adhesion and cell motility regulation, and to downregulation of the actin-bundling protein fascin.…”

Section: Introductionmentioning

confidence: 99%

miR-145-dependent targeting of Junctional Adhesion Molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness

et al. 2010

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Micro RNAs are small non-coding RNAs, which regulate fundamental cellular and developmental processes at the transcriptional and translational level. In breast cancer, miR-145 expression is downregulated compared with healthy control tissue. As several predicted targets of miR-145 potentially regulate cell motility, we aimed at investigating a potential role for miR-145 in breast cancer cell motility and invasiveness. Assisted by Affymetrix array technology, we demonstrate that overexpression of miR-145 in MDA-MB-231, MCF-7, MDA-MB-468 and SK-BR-3 breast cancer cells and in Ishikawa endometrial carcinoma cells leads to a downregulation of the cell-cell adhesion protein JAM-A and of the actin bundling protein fascin. Moreover, podocalyxin and Serpin E1 mRNA levels were downregulated, and gamma-actin, transgelin and MYL9 were upregulated upon miR-145 overexpression. These miR-145-dependent expression changes drastically decreased cancer cell motility, as revealed by time-lapse video microscopy, scratch wound closure assays and matrigel invasion assays. Immunofluorescence microscopy demonstrated restructuring of the actin cytoskeleton and a change in cell morphology by miR-145 overexpression, resulting in a more cortical actin distribution, and reduced actin stress fiber and filopodia formation. Nuclear rotation was observed in 10% of the pre-miR-145 transfected MDA-MB-231 cells, accompanied by a reduction of perinuclear actin. Luciferase activation assays confirmed direct miR-145-dependent regulation of the 3 0 UTR of JAM-A, whereas siRNA-mediated knockdown of JAM-A expression resulted in decreased motility and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. Our data identify JAM-A and fascin as novel targets of miR-145, firmly establishing a role for miR-145 in modulating breast cancer cell motility. Our data provide a rationale for future miR-145-targeted approaches of antimetastatic cancer therapy.

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miR-145 directs intestinal maturation in zebrafish

Cited by 63 publications

References 41 publications

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

Regulation of mouse stomach development and Barx1 expression by specific microRNAs

miR-145-dependent targeting of Junctional Adhesion Molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness

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