Nkx-2.5 Gene Induction in Mice Is Mediated by a Smad Consensus Regulatory Region

Liberatore, Christine M.; Searcy-Schrick, Robin D.; Vincent, Eric B.; Yutzey, Katherine E.

doi:10.1006/dbio.2002.0604

Cited by 89 publications

(59 citation statements)

References 63 publications

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“…Although several BMP responsive elements have been characterized in cultured cells (Benchabane and Wrana, 2003;Henningfeld et al, 2000;Hullinger et al, 2001;Jonk et al, 1998), few have been studied in a developing mammalian embryo (Liberatore et al, 2002;Lien et al, 2002;Theil et al, 2002). The Msx2 BMP-dependent enhancer is of particular interest because of the importance of Msx2 in the BMP pathway and because Msx2 is frequently employed as a readout of BMP action, despite the fact that the mechanisms controlling its BMP responsiveness have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

A phylogenetically conserved cis-regulatory module in theMsx2promoter is sufficient for BMP-dependent transcription in murine andDrosophilaembryos

et al. 2004

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To understand the actions of morphogens, it is crucial to determine how they elicit different transcriptional responses in different cell types. Here,we identify a BMP-responsive enhancer of Msx2, an immediate early target of bone morphogenetic protein (BMP) signaling. We show that the BMP-responsive region of Msx2 consists of a core element, required generally for BMP-dependent expression, and ancillary elements that mediate signaling in diverse developmental settings. Analysis of the core element identified two classes of functional sites: GCCG sequences related to the consensus binding site of Mad/Smad-related BMP signal transducers; and a single TTAATT sequence, matching the consensus site for Antennapedia superclass homeodomain proteins. Chromatin immunoprecipitation and mutagenesis experiments indicate that the GCCG sites are direct targets of BMP restricted Smads. Intriguingly, however, these sites are not sufficient for BMP responsiveness in mouse embryos; the TTAATT sequence is also required. DNA sequence comparisons reveal this element is highly conserved in Msx2promoters from mammalian orders but is not detectable in other vertebrates or non-vertebrates. Despite this lack of conservation outside mammals, the Msx2 BMP-responsive element serves as an accurate readout of Dpp signaling in a distantly related bilaterian – Drosophila. Strikingly, in Drosophila embryos, as in mice, both TTAATT and GCCG sequences are required for Dpp responsiveness, showing that a common cis-regulatory apparatus can mediate the transcriptional activation of BMP-regulated genes in widely divergent bilaterians.

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Section: Discussionmentioning

confidence: 99%

A phylogenetically conserved cis-regulatory module in theMsx2promoter is sufficient for BMP-dependent transcription in murine andDrosophilaembryos

et al. 2004

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“…The Ϫ301/Ϫ277 region of the promoter contains putative Smadand GATA-binding sites. The function of these putative regulatory elements in myocardial differentiation is highly conserved (Molkentin, 2000;Liberatore et al, 2002;Peterkin et al, 2005;Qi et al, 2007;Song et al, 2007). A single nucleotide substitution (Ϫ287/ C3 T) of the putative GATA-binding site of vmhc promoter region led to a MO-injected (D; MO6), GATA4 and GATA5 MO-injected (E; MO4ϩ5), GATA4 and GATA6 MOinjected (F; MO4ϩ6), GATA5 and GATA6 MO-injected (G; MO5ϩ6), GATA4, GATA5 and GATA6 MO-injected (H; MO4ϩ5ϩ6) embryos.…”

Section: Gata Site As a Critical Upstream Element Of Vmhc Promoter Acmentioning

confidence: 99%

Isolation of a ventricle‐specific promoter for the zebrafish ventricular myosin heavy chain (vmhc) gene and its regulation by GATA factors during embryonic heart development

Park

Kim

et al. 2009

Developmental Dynamics

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We investigated chamber-specific gene expression by isolating a 2.2-kb polymerase chain reaction product containing the 5-flanking region of the zebrafish ventricular myosin heavy-chain gene (vmhc). Promoter analysis revealed that the fragment, consisting of nucleotides from ؊301 to ؉26, is sufficient for vmhc promoter activity. Among several putative cis-acting elements in the region, a GATA-binding site was identified to be crucial for the activity of the promoter, as evidenced by the complete abolishment of promoter activity by a single nucleotide substitution of GATA-binding site (؊287, C3 T). Knockdown of GATA-binding proteins 4 and 6 (GATA4 and -6) by their antisense morpholino oligonucleotides resulted in reduced green fluorescent protein (GFP) reporter gene and endogenous vmhc expression. These findings suggest that GATA4 and -6 play a key role in the regulation of vmhc expression in the ventricle. In addition, the vmhc promoter and the transgenic zebrafish (vmhc:gfp) are useful tools to study the formation and function of the ventricle. Developmental Dynamics 238:1574 -1581, 2009.

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“…The BRE contains two GC-rich elements and two CAGAG boxes that act cooperatively to confer BMP responsiveness the Hex promoter. A similar BRE element is present within the BMP-responsive Nkx2-5 gene promoter (52,55), suggesting that the Hex BRE represents a common response element for genes regulated by BMP signaling in the foregut region of the embryo.…”

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confidence: 99%

Regulation of Hex Gene Expression by a Smads-dependent Signaling Pathway

Zhang

Yatskievych

Cao

et al. 2002

Journal of Biological Chemistry

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The homeobox gene Hex is expressed in multiple cell types during embryogenesis and is required for liver and monocyte development. Hex is expressed in the foregut region of late gastrula avian and mammalian embryos in a pattern that overlaps with expression of bone morphogenetic proteins (BMPs). Here we investigate the relationship between BMP signaling and Hex gene expression. We find that Hex expression in avian anterior lateral endoderm is regulated by autocrine BMP signaling. Characterization of the mouse Hex gene promoter identified a 71-nucleotide BMP-responsive element (BRE) that is required for up-regulation of Hex by an activated BMP signaling pathway. The Hex BRE binds Smad4 and Smad1-Smad4 complexes in vitro, and in transfection assays, it is responsive to Smad1 and Smad4 but not to Smad2 and Smad4 or Smad3 and Smad4. The BRE contains two copies of a GCCGnCGClike motif that in Drosophila is the binding site for Mad and Madea followed by two CAGAG boxes that are similar to sequences required for transforming growth factor-␤/activin responsiveness of several vertebrate genes. Mutation of the GC elements, but not the two CAGAG boxes, abolishes Smads responsiveness in the intact Hex promoter, whereas mutations in both the GC elements and CAGAG boxes show that they act cooperatively to confer Smads responsiveness to the Hex promoter. The Hex BRE can confer Smads responsiveness to a heterologous promoter, and in this context, both the GC-rich elements and the CAGAG boxes are required for Smadsdependent promoter activity. An element almost identical to the Hex BRE is present within the BMP-responsive Nkx2-5 gene promoter, suggesting that the Hex BRE represents a common response element for genes regulated by BMP signaling in the foregut region of the embryo.The transforming growth factor (TGF␤) 1 superfamily of signaling molecules, including bone morphogenetic proteins (BMPs), TGF␤s, activins, inhibins, and mullerian-inhibiting substance, regulate a wide range of biological processes during embryonic development and in the adult (1). BMPs were first identified due to their ability to induce cartilage and bone formation (2) and have subsequently been shown to regulate many aspects of embryogenesis, including early patterning of the embryo (3-5).Like other TGF␤ family members, BMPs exert their biological effects by binding to heteromeric complexes of type I and type II serine/kinase receptors (6). The type II receptor kinase activates the type I receptor kinase, which in turn phosphorylates members of the Smad protein family that are responsible for transducing receptor-mediated signals to the nucleus (7). Smad proteins fall generally into three classes: receptor-regulated Smads (R-Smads); the co-Smad, Smad4; and the inhibitory Smads (I-Smads), Smad6 and Smad7. The R-Smads Smad2 and Smad3 are preferentially phosphorylated by TGF␤ and type I activin receptors, whereas BMPs preferentially induce phosphorylation of Smad1, Smad5, and Smad8. Phosphorylated R-Smads dissociate from the type I receptor, bind to Smad4 ...

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Nkx-2.5 Gene Induction in Mice Is Mediated by a Smad Consensus Regulatory Region

Cited by 89 publications

References 63 publications

A phylogenetically conserved cis-regulatory module in theMsx2promoter is sufficient for BMP-dependent transcription in murine andDrosophilaembryos

A phylogenetically conserved cis-regulatory module in theMsx2promoter is sufficient for BMP-dependent transcription in murine andDrosophilaembryos

Isolation of a ventricle‐specific promoter for the zebrafish ventricular myosin heavy chain (vmhc) gene and its regulation by GATA factors during embryonic heart development

Regulation of Hex Gene Expression by a Smads-dependent Signaling Pathway

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