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

Trembley, Michael A.; Velasquez, Lissette S.; Bentley, Karen L. de Mesy; Small, Eric M.

doi:10.1242/dev.116418

Cited by 77 publications

(75 citation statements)

References 58 publications

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“…TGF-β is known to promote the assembly of stress fibers in a Rho GTPase A (Rho-A)-and Rho Kinase (ROCK)-dependent manner, which leads to the nuclear localization of MRTF-A, and subsequent induction of focal adhesion and contractile genes, such as α-SMA (Cen et al, 2003;Crider et al, 2011;Sandbo et al, 2011;Small et al, 2010;Trembley et al, 2015;Zhao et al, 2007). These data support a model in which stress fiber formation is not only a consequence but also a crucial regulator of myofibroblast differentiation.…”

Section: Introductionsupporting

confidence: 57%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.

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Section: Introductionsupporting

confidence: 57%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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“…To test this hypothesis, MYOSLID expression was depleted with siRNA in HCASMCs followed by TGFβ1 treatment to stimulate nuclear translocation of MKL1. 34 F-actin assembly was disrupted upon MYOSLID knockdown in both vehicle and TGFβ1 treated groups (Figure 5B). Further, forced expression of MYOSLID_V1 rescued F-actin formation in HCASMCs when SRF was depleted although no obvious differences were seen under the basal conditions (Figure VI in the online-only Data Supplement).…”

Section: Resultsmentioning

confidence: 95%

MYOSLID Is a Novel Serum Response Factor–Dependent Long Noncoding RNA That Amplifies the Vascular Smooth Muscle Differentiation Program

Zhao

Zhang

Lin

et al. 2016

ATVB

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Objective Long noncoding RNAs (lncRNA) represent a growing class of noncoding genes with diverse cellular functions. We previously reported on SENCR, a lncRNA that appears to support the vascular smooth muscle cell (VSMC) contractile phenotype. However, information about the vascular smooth muscle cell (VSMC)-specific lncRNAs regulated by myocardin (MYOCD)/SRF, the master switch for VSMC differentiation, is virtually unknown. Approach and Results To define novel lncRNAs with functions related to VSMC differentiation, we performed RNA sequencing in human coronary artery SMCs (HCASMCs) that overexpress MYOCD. A number of novel lncRNAs showed altered expression with MYOCD overexpression and one, named MYOcardin-induced Smooth muscle Long non-coding RNA, Inducer of Differentiation (MYOSLID), was activated by MYOCD and selectively expressed in VSMCs. MYOSLID was a direct transcriptional target of both MYOCD/SRF and TGFβ/SMAD pathways. Functional studies revealed that MYOSLID promotes VSMC differentiation and inhibits VSMC proliferation. MYOSLID showed reduced expression in failed human arteriovenous fistula (AVF) samples compared with healthy veins. While MYOSLID did not affect gene expression of transcription factors such as SRF and MYOCD, its depletion in VSMCs disrupted actin stress fiber formation and blocked nuclear translocation of MYOCD-related transcription factor A (MKL1). Finally, loss of MYOSLID abrogated TGFβ1-induced SMAD2 phosphorylation. Conclusion We have demonstrated that MYOSLID, the first human VSMC-selective and SRF/CArG-dependent lncRNA, is a novel modulator in amplifying the VSMC differentiation program, likely through feed-forward actions of both MKL1 and TGFβ/SMAD pathways.

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“…The similarity between the phenotypes of mice in which MRTF-A and MRTF-B or myocardin were deleted with αMHC-Cre suggests that they may play similar roles in cardiac development and function. In addition to their cardiomyocyte-specific functions, MRTFs have been shown to play other roles in the heart, including activation of the cardiac fibrotic gene program (Small et al, 2010) and coronary vascular development and maturation (Trembley et al, 2015), while functions for myocardin and MRTFs in smooth muscle differentiation and development have been extensively investigated (S. Li et al, 2006; 2003; Oh et al, 2005; Z.…”

Section: Discussionmentioning

confidence: 99%

Myocardin-related transcription factors are required for cardiac development and function

Mokalled

Carroll

Cenik

et al. 2015

Developmental Biology

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Myocardin-Related Transcription Factors A and B (MRTF-A and MRTF-B) are highly homologous proteins that function as powerful coactivators of serum response factor (SRF), a ubiquitously expressed transcription factor essential for cardiac development. The SRF/MRTF complex binds to CArG boxes found in the control regions of genes that regulate cytoskeletal dynamics and muscle contraction, among other processes. While SRF is required for heart development and function, the role of MRTFs in the developing or adult heart has not been explored. Through cardiac-specific deletion of MRTF alleles in mice, we show that either MRTF-A or MRTF-B is dispensable for cardiac development and function, whereas deletion of both MRTF-A and MRTF-B causes a spectrum of structural and functional cardiac abnormalities. Defects observed in MRTF-A/B null mice ranged from reduced cardiac contractility and adult onset heart failure to neonatal lethality accompanied by sarcomere disarray. RNA-seq analysis on neonatal hearts identified the most altered pathways in MRTF double knockout hearts as being involved in cytoskeletal organization. Together, these findings demonstrate redundant but essential roles of the MRTFs in maintenance of cardiac structure and function and as indispensible links in cardiac cytoskeletal gene regulatory networks.

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

Cited by 77 publications

References 58 publications

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

MYOSLID Is a Novel Serum Response Factor–Dependent Long Noncoding RNA That Amplifies the Vascular Smooth Muscle Differentiation Program

Myocardin-related transcription factors are required for cardiac development and function

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