Actin-mediated gene expression in neurons: the MRTF-SRF connection

2010 ◽  
Vol 391 (6) ◽  
Author(s):  
Bernd Knöll
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Serum Response Factor ◽  
Actin Dynamics ◽  
Response Factor ◽  
Related Transcription Factor ◽  
Gene Regulatory ◽  
Regulatory Loop ◽  
Serum Response ◽  
Prime Target

Abstract The traditional view of cellular actin is a rather autarkic cytoskeletal framework function confined to the cytoplasm. However, there is now evidence that alterations in actin dynamics are sensed by the nucleus and subsequently modulate gene expression. In communicating with the nucleus, cytoplasmic, and most likely also nucleus-resident actin, provides a further (gene) regulatory loop to cell motility. A transcription module composed of MRTF (myocardin-related transcription factor) and SRF (serum response factor) emerges as prime target of such actin signaling. Here, I focus on the nervous system, where the actin-MRTF-SRF entity governs multiple aspects of neuronal motility.

scholarly journals Serum response factor: positive and negative regulation of an epithelial gene expression network in the destrin mutant cornea

2014 ◽  
Vol 46 (8) ◽  
pp. 277-289 ◽  
Author(s):  
Sharolyn V. Kawakami-Schulz ◽  
Angela M. Verdoni ◽  
Shannon G. Sattler ◽  
Erik Jessen ◽  
Winston W.-Y. Kao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Networks ◽  
Serum Response Factor ◽  
Conditional Knockout ◽  
Cell Junctions ◽  
Actin Dynamics ◽  
Response Factor ◽  
In Vivo Models ◽  
Serum Response

Increased angiogenesis, inflammation, and proliferation are hallmarks of diseased tissues, and in vivo models of these disease phenotypes can provide insight into disease pathology. Dstn corn1 mice, deficient for the actin depolymerizing factor destrin (DSTN), display an increase of serum response factor (SRF) that results in epithelial hyperproliferation, inflammation, and neovascularization in the cornea. Previous work demonstrated that conditional ablation of Srf from the corneal epithelium of Dstn corn1 mice returns the cornea to a wild-type (WT) like state. This result implicated SRF as a major regulator of genes that contributes to abnormal phenotypes in Dstn corn1 cornea. The purpose of this study is to identify gene networks that are affected by increased expression of Srf in the Dstn corn1 cornea. Microarray analysis led to characterization of gene expression changes that occur when conditional knockout of Srf rescues mutant phenotypes in the cornea of Dstn corn1 mice. Comparison of gene expression values from WT, Dstn corn1 mutant, and Dstn corn1 rescued cornea identified >400 differentially expressed genes that are downstream from SRF. Srf ablation had a significant effect on genes associated with epithelial cell-cell junctions and regulation of actin dynamics. The majority of genes affected by SRF are downregulated in the Dstn corn1 mutant cornea, suggesting that increased SRF negatively affects transcription of SRF gene targets. ChIP-seq analysis on Dstn corn1 mutant and WT tissue revealed that, despite being present in higher abundance, SRF binding is significantly decreased in the Dstn corn1 mutant cornea. This study uses a unique model combining genetic and genomic approaches to identify genes that are regulated by SRF. These findings expand current understanding of the role of SRF in both normal and abnormal tissue homeostasis.

scholarly journals Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

2012 ◽  
Vol 109 (38) ◽  
pp. E2523-E2532 ◽  
Author(s):  
Henning Beck ◽  
Kevin Flynn ◽  
Katrin S. Lindenberg ◽  
Heinz Schwarz ◽  
Frank Bradke ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Serum Response Factor ◽  
Mitochondrial Dynamics ◽  
Actin Dynamics ◽  
Response Factor ◽  
Signaling Axis ◽  
Mitochondrial Number ◽  
Mitochondrial Networks ◽  
The Impact ◽  
Serum Response

Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.

scholarly journals The Cytoskeleton-associated PDZ-LIM Protein, ALP, Acts on Serum Response Factor Activity to Regulate Muscle Differentiation

2007 ◽  
Vol 18 (5) ◽  
pp. 1723-1733 ◽  
Author(s):  
Pascal Pomiès ◽  
Mohammad Pashmforoush ◽  
Cristina Vegezzi ◽  
Kenneth R. Chien ◽  
Charles Auffray ◽  
...  
Keyword(s):  
Serum Response Factor ◽  
Critical Role ◽  
Muscle Differentiation ◽  
Actin Dynamics ◽  
Response Factor ◽  
Cytoskeletal Regulation ◽  
Expression Construct ◽  
Filament Bundles ◽  
Serum Response

In this report, an antisense RNA strategy has allowed us to show that disruption of ALP expression affects the expression of the muscle transcription factors myogenin and MyoD, resulting in the inhibition of muscle differentiation. Introduction of a MyoD expression construct into ALP-antisense cells is sufficient to restore the capacity of the cells to differentiate, illustrating that ALP function occurs upstream of MyoD. It is known that MyoD is under the control of serum response factor (SRF), a transcriptional regulator whose activity is modulated by actin dynamics. A dramatic reduction of actin filament bundles is observed in ALP-antisense cells and treatment of these cells with the actin-stabilizing drug jasplakinolide stimulates SRF activity and restores the capacity of the cells to differentiate. Furthermore, we show that modulation of ALP expression influences SRF activity, the level of its coactivator, MAL, and muscle differentiation. Collectively, these results suggest a critical role of ALP on muscle differentiation, likely via cytoskeletal regulation of SRF.

scholarly journals New Role for Serum Response Factor in Postnatal Skeletal Muscle Growth and Regeneration via the Interleukin 4 and Insulin-Like Growth Factor 1 Pathways

2006 ◽  
Vol 26 (17) ◽  
pp. 6664-6674 ◽  
Author(s):  
Claude Charvet ◽  
Christophe Houbron ◽  
Ara Parlakian ◽  
Julien Giordani ◽  
Charlotte Lahoute ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Serum Response Factor ◽  
Muscle Growth ◽  
Interleukin 4 ◽  
Specific Gene ◽  
Response Factor ◽  
Insulin Like Growth Factor ◽  
Serum Response

ABSTRACT Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.

Alternative splicing and nonsense-mediated mRNA decay regulate gene expression of serum response factor

Gene ◽  
2007 ◽  
Vol 400 (1-2) ◽  
pp. 131-139 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Chris Huang ◽  
Cunqi Cui ◽  
Ying Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mrna Decay ◽  
Serum Response Factor ◽  
Response Factor ◽  
Regulate Gene Expression ◽  
Nonsense Mediated Mrna Decay ◽  
Serum Response ◽  
Regulate Gene

scholarly journals Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.

1993 ◽  
Vol 13 (2) ◽  
pp. 1264-1272 ◽  
Author(s):  
C K Vincent ◽  
A Gualberto ◽  
C V Patel ◽  
K Walsh
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Creatine Kinase ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Sequence Motif ◽  
Regulatory Sequences ◽  
Response Factor ◽  
Specific Expression ◽  
Serum Response

Regulatory sequences of the M isozyme of the creatine kinase (MCK) gene have been extensively mapped in skeletal muscle, but little is known about the sequences that control cardiac-specific expression. The promoter and enhancer sequences required for MCK gene expression were assayed by the direct injection of plasmid DNA constructs into adult rat cardiac and skeletal muscle. A 700-nucleotide fragment containing the enhancer and promoter of the rabbit MCK gene activated the expression of a downstream reporter gene in both muscle tissues. Deletion of the enhancer significantly decreased expression in skeletal muscle but had no detectable effect on expression in cardiac muscle. Further deletions revealed a CArG sequence motif at position -179 within the promoter that was essential for cardiac-specific expression. The CArG element of the MCK promoter bound to the recombinant serum response factor and YY1, transcription factors which control expression from structurally similar elements in the skeletal actin and c-fos promoters. MCK-CArG-binding activities that were similar or identical to serum response factor and YY1 were also detected in extracts from adult cardiac muscle. These data suggest that the MCK gene is controlled by different regulatory programs in adult cardiac and skeletal muscle.

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

2016 ◽  
Vol 36 (10) ◽  
pp. 1526-1539 ◽  
Author(s):  
Julia Weissbach ◽  
Franziska Schikora ◽  
Anja Weber ◽  
Michael Kessels ◽  
Guido Posern
Keyword(s):  
Serum Response Factor ◽  
De Novo ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Serum Stimulation ◽  
Competitive Mechanism ◽  
Related Transcription Factor ◽  
Simultaneous Inhibition ◽  
Serum Response

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.

scholarly journals Serum Response Factor Regulates Immediate Early Host Gene Expression in Toxoplasma gondii-Infected Host Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (3) ◽  
pp. e18335 ◽  
Author(s):  
Mandi Wiley ◽  
Crystal Teygong ◽  
Eric Phelps ◽  
Jay Radke ◽  
Ira J. Blader
Keyword(s):  
Gene Expression ◽  
Toxoplasma Gondii ◽  
Serum Response Factor ◽  
Host Gene ◽  
Host Cells ◽  
Immediate Early ◽  
Infected Host ◽  
Response Factor ◽  
Host Gene Expression ◽  
Serum Response

scholarly journals OTT-MAL Is a Deregulated Activator of Serum Response Factor-Dependent Gene Expression

2008 ◽  
Vol 28 (20) ◽  
pp. 6171-6181 ◽  
Author(s):  
Arnaud Descot ◽  
Monika Rex-Haffner ◽  
Geneviève Courtois ◽  
Dominique Bluteau ◽  
Antje Menssen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Serum Response Factor ◽  
Mitogen Activated Protein Kinase ◽  
Binding Motif ◽  
Fusion Partner ◽  
Response Factor ◽  
Transactivation Domain ◽  
Regulated Gene Expression ◽  
Serum Response

ABSTRACT The OTT-MAL/RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytic leukemia in infants. How it contributes to the malignancy is unknown. The 3′ fusion partner, MAL/MKL1/MRTF-A, is a transcriptional coactivator of serum response factor (SRF). MAL plays a key role in regulated gene expression depending on Rho family GTPases and G-actin. Here we demonstrate that OTT-MAL is a constitutive activator of SRF and target gene expression. This requires the SRF-binding motif and the MAL-derived transactivation domain. OTT-MAL localizes to the nucleus and is not regulated by upstream signaling. OTT-MAL deregulation reflects its independence from control by G-actin, which fails to interact with OTT-MAL in coimmunoprecipitation experiments. Regulation cannot be restored by reintroduction of the entire MAL N terminus into the fusion protein. OTT-MAL also caused a delayed induction of the MAL-independent, ternary complex factor-dependent target genes c-fos and egr-1 and the mitogen-activated protein kinase/Erk pathway. With testing in heterologous tissue culture systems, however, we observed considerable antiproliferative effects of OTT-MAL. Our data suggest that the deregulated activation of MAL-dependent and -independent promoters results in tissue-specific functions of OTT-MAL.

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