MRTFA: A critical protein in normal and malignant hematopoiesis and beyond

Reed, Fiona; Larsuel, Shannon T.; Mayday, Madeline Y; Scanlon, Vanessa; Krause, Diane S.

doi:10.1016/j.jbc.2021.100543

Cited by 17 publications

(24 citation statements)

References 92 publications

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“…Endogenous stimuli known to control MKL1 activity include receptor-mediated signal transduction, the mechanical milieu, and nuclear lamina properties (28). Receptor engagement by the megakaryopoietic cytokine thrombopoietin induces rapid and transient MKL1 nuclear translocation in primary murine megakaryocytic progenitors in suspension culture (30).…”

Section: Discussionmentioning

confidence: 99%

“…functions as a coactivator of the SRF (serum response factor) transcription factor in programming differentiation of multiple cell types including multiple muscle and hematopoietic lineages. It exerts these functions through control of genes involved in actin cytoskeleton remodeling and is in turn regulated by cytoskeletal status, with monomeric G-actin (globular) preventing its nuclear localization (28). MKL1 plays a critical role in driving adult megakaryocyte morphogenesis and undergoes upregulation and nuclear translocation in response to the megakaryopoietic cytokine thrombopoietin (28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

Elagib¹,

Brock²,

Clementelli³

et al. 2022

Journal of Clinical Investigation

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Infantile (fetal and neonatal) megakaryocytes have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived megakaryocytes.The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with potential to affect MKL1 function and found that Dyrk1a kinase inhibition dramatically enhanced megakaryocyte morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal megakaryocytes. Megakaryocytes derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss of function studies confirmed MKL1 involvement in this morphogenetic pathway. Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results thus delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile megakaryocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

Elagib¹,

Brock²,

Clementelli³

et al. 2022

Journal of Clinical Investigation

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“…These genes could potentially be used as markers for the response of T cells to MG and to HS (Supplementary Figure S3). MKL1/MRTFA encodes an actin sensor that upon decreased G-actin enters into the nucleus and interacts with the serum response factor (SRF) to drive transcription of actin network genes [13,14]. VAV1, VAV2 and VAV3 all followed the same trend in gene expression.…”

Section: Mg<hs Mg>hs Mg=hsmentioning

confidence: 99%

“…The copyright holder for this this version posted October 21, 2021. ; https://doi.org/10.1101/2021.10.20.465119 doi: bioRxiv preprint proteins and is involved in several critical processes including cell growth and motility, apoptosis and cancer progression [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…In the context of cytoskeletal regulation, it was especially interesting that a majority of the genes that were inhibited in T cells in microgravity contains DNA serum response elements (SRE) in the promoters that binds the serum response factor (SRF) [10] as a part of transcriptionally active SRF/MRTFA complex. The SRF/MRTFA transcription factor plays a key role in actin cytoskeleton organization by targeting the transcription of genes encoding cytoskeletal proteins and is involved in several critical processes including cell growth and motility, apoptosis and cancer progression [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Cell responses to simulated microgravity and hydrodynamic stress can be distinguished by using comparative transcriptomic analysis

Kouznetsov

2021

Preprint

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The human immune system is compromised in microgravity (MG) conditions during an orbital flight and upon return to Earth. T cells are critical for the immune response and execute their functions via actin mediated immune cell-cell interactions that could be disturbed by MG conditions. Here, we have applied two rotational platforms to simulate MG conditions: fast rotating clinostat (CL) and random positioning machine (RPM) followed by global T cell transcriptome analysis using RNA sequencing. We demonstrate that the T cell transcriptome profile in response to simulated MG treatment was clearly distinguishable from the T cell transcriptome response to hydrodynamic stress (HS) induced by shear forces upon cell movement in cultural medium. Gene expression profiling of genes related to or involved in actin cytoskeleton networks using RT-qPCR confirmed two sets of differentially regulated genes in the T cell response to MG or to HS. Several key genes potentially involved in T cell gravisensing (Fam163b, Dnph1, Trim34, Upk-1b) were identified. A number of candidate biomarker genes of the response to MG (VAV1, VAV2, VAV3, and NFATC2) and of the response to HS (ITGAL, ITGB1, ITGB2, RAC1 and RAC2) could be used to distinguish between these processes on the gene transcription level. Together, MG induces changes in the overall transcriptome of T cells leading to specific shifts in expression of cytoskeletal network genes.

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Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche

Krauss

Kann

2023

BioEssays

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Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings.

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MRTFA: A critical protein in normal and malignant hematopoiesis and beyond

Cited by 17 publications

References 92 publications

Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

Cell responses to simulated microgravity and hydrodynamic stress can be distinguished by using comparative transcriptomic analysis

Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche

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