MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

Hinkel, Rabea; Trenkwalder, Teresa; Petersen, Björn; Husada, Wira; Gesenhues, Florian; Lee, Seungmin; Hannappel, Ewald; Bock-Marquette, Ildiko; Theisen, Daniel; Leitner, Laura; Boekstegers, Peter; Cierniewski, Czesław S.; Müller, Oliver; Noble, Ferdinand le; Adams, Ralf H.; Weinl, Christine; Nordheim, Alfred; Reichart, Bruno; Weber, Christian; Olson, Eric N.; Posern, Guido; Deindl, Elisabeth; Niemann, Heiner; Kupatt, Christian

doi:10.1038/ncomms4970

Cited by 82 publications

(66 citation statements)

References 52 publications

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“…For the N-WASP and WAVE2 WH2 domains, the activation was further enhanced by the presence of the Arp2/3-activating central and acidic (CA) regions. However, thymosin ␤4, which resembles an individual WH2 domain without any nucleation activity, also activated MRTF-mediated transcription strongly, in line with our previous findings (9).…”

Section: Resultssupporting

confidence: 80%

Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

Weißbach

Schikora

Weber

et al. 2016

Molecular and Cellular Biology

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The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin–MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear. Here we show that WH2 domains compete directly with MRTF-A for actin binding. Actin nucleation-promoting factors, such as N-WASP and WAVE2, as well as isolated WH2 domains, including those of Spire2 and Cobl, activate MRTF-A independently of changes in actin dynamics. Simultaneous inhibition of Arp2-Arp3 or mutation of the CA region only partially reduces MRTF-A activation by N-WASP and WAVE2. Recombinant WH2 domains and the RPEL domain of MRTF-A bind mutually exclusively to cellular and purified G-actinin vitro. The competition by different WH2 domains correlates with MRTF-SRF activation. Following serum stimulation, nonpolymerizable actin dissociates from MRTF-A, andde novoformation of the G-actin–RPEL complex is impaired by a transferable factor. Our work demonstrates that WH2 domains activate MRTF-A and contribute to target gene regulation by a competitive mechanism, independently of their role in actin filament formation.

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Section: Resultssupporting

confidence: 80%

Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

Weißbach

Schikora

Weber

et al. 2016

Molecular and Cellular Biology

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“…Given that the epicardium is made up of a heterogeneous population of progenitor cells with the capacity to give rise to multiple cardiac cell types, it is conceivable that MRTFs also control EC differentiation and migration directly, as reported in the postnatal retinal vasculature and adult neoangiogenesis (Hinkel et al, 2014;Weinl et al, 2013). However, our current study confirms previous findings that coronary ECs originating from the sub-epicardium are primarily descendants of a Wt1…”

Section: Discussionsupporting

confidence: 54%

Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels

et al. 2015

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An important pool of cardiovascular progenitor cells arises from the epicardium, a single layer of mesothelium lining the heart. Epicardiumderived progenitor cell (EPDC) formation requires epithelial-tomesenchymal transition (EMT) and the subsequent migration of these cells into the sub-epicardial space. Although some of the physiological signals that promote EMT are understood, the functional mediators of EPDC motility and differentiation are not known. Here, we identify a novel regulatory mechanism of EPDC mobilization. Myocardin-related transcription factor (MRTF)-A and MRTF-B (MKL1 and MKL2, respectively) are enriched in the perinuclear space of epicardial cells during development. Transforming growth factor (TGF)-β signaling and disassembly of cell contacts leads to nuclear accumulation of MRTFs and the activation of the motile gene expression program. Conditional ablation of Mrtfa and Mrtfb specifically in the epicardium disrupts cell migration and leads to subepicardial hemorrhage, partially stemming from the depletion of coronary pericytes. Using lineage-tracing analyses, we demonstrate that sub-epicardial pericytes arise from EPDCs in a process that requires the MRTF-dependent motile gene expression program. These findings provide novel mechanisms linking EPDC motility and differentiation, shed light on the transcriptional control of coronary microvascular maturation and suggest novel therapeutic strategies to manipulate epicardium-derived progenitor cells for cardiac repair.

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“…CCN1 in turn serves multiple functions. Microvessel growth in ischemic muscle was linked to increased expression of CCN1 and its proangiogenic properties (Hinkel et al, 2014). CCN1 is also upregulated in a liver injury model along with myofibroblast markers, such as a-SMA .…”

Section: Pathophysiological Consequences Of Gpcr-and Rhoa-mediated Trmentioning

confidence: 94%

“…Neovascularization in the murine ischemic hindlimb model has been shown to be mediated through MRTF-A (Hinkel et al, 2014), as has retinal vascularization in the postnatal mouse eye (Weinl et al, 2013). Although these MRTF-A-mediated responses have not been linked to GPCR signaling, GPCR signaling through G 13 was recently demonstrated to play a critical role in the development of in vivo retinal angiogenesis, which is mediated through effects of NFkB and subsequent expression of vascular endothelial growth factor receptor 2 (Sivaraj et al, 2013).…”

Section: Pathophysiological Consequences Of Gpcr-and Rhoa-mediated Trmentioning

confidence: 99%

G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

Brown

2015

Mol Pharmacol

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The low molecular weight G protein RhoA (rat sarcoma virus homolog family member A) serves as a node for transducing signals through G protein-coupled receptors (GPCRs). Activation of RhoA occurs through coupling of G proteins, most prominently, G 12/13 , to Rho guanine nucleotide exchange factors. The GPCR ligands that are most efficacious for RhoA activation include thrombin, lysophosphatidic acid, sphingosine-1-phosphate, and thromboxane A2. These ligands also stimulate proliferation, differentiation, and inflammation in a variety of cell and tissues types. The molecular events underlying these responses are the activation of transcription factors, transcriptional coactivators, and downstream gene programs. This review describes the pathways leading from GPCRs and RhoA to the regulation of activator protein-1, NFkB (nuclear factor k-light-chain-enhancer of activated B cells), myocardin-related transcription factor A, and Yes-associated protein. We also focus on the importance of two prominent downstream transcriptional gene targets, the inflammatory mediator cyclooxygenase 2, and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN1). Finally, we describe the importance of GPCR-induced activation of these pathways in the pathophysiology of cancer, fibrosis, and cardiovascular disease.

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MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

Cited by 82 publications

References 52 publications

Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding

Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels

G Protein–Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation

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