MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation

Smith, Elenoe C.; Thon, Jonathan N.; Devine, Matthew T.; Lin, Sharon; Schulz, Vincent P.; Guo, Yanwen; Massaro, Stephanie A.; Halene, Stephanie; Gallagher, Patrick G.; Italiano, Joseph E.; Krause, Diane S.

doi:10.1182/blood-2012-04-420828

Cited by 54 publications

(78 citation statements)

References 46 publications

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“…In agreement, knocking down either MYOCD or MRTF-A and -B decreased CDH11-mediated expression of collagen and elastin, but the effects of MRTF-A and -B were significantly stronger. Although past studies have only recognized MRTF and MYOCD as co-activators of SRF, some recent studies have shown that they can act as transcription factors independently (Tang et al, 2008;Asparuhova et al, 2011;Luchsinger et al, 2011;Smith et al, 2012;Kitchen et al, 2013). MRTF-A has been shown to control Col1A2 promoter activity as well as expression of other extracellular matrix molecules (Asparuhova et al, 2011;Luchsinger et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Row

Liu

Alimperti

et al. 2016

Journal of Cell Science

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We discovered that Cadherin-11 (CDH11) regulates collagen and elastin synthesis, both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11-null mouse model, we observed a significant reduction in the mechanical properties [Youngs' modulus and ultimate tensile strength (UTS)] of Cdh11 −/− as compared to wild-type (WT) mouse tissues, such as the aorta, bladder and skin. The deterioration of mechanical properties (Youngs' modulus and UTS) was accompanied by reduced collagen and elastin content in Cdh11 −/− mouse tissues as well as in cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-β and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of the key transcription factors, MRTF-A (also known as MKL1) and MYOCD led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating extracellular matrix (ECM) synthesis with implications for many important biological processes, including maintenance of tissue integrity, wound healing and tissue regeneration.

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Section: Discussionmentioning

confidence: 99%

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Row

Liu

Alimperti

et al. 2016

Journal of Cell Science

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“…[30][31][32] Recently, the first case of a homozygous mutation in MKL1 in a patient with severe immunodeficiency and no hematologic malignancies was reported. 33 One interesting phenotypic presentation of the affected individual was an intermittent mild thrombocytopenia with low platelet counts in whole blood of between 50x10 9 /L and 150x10 9 /L.…”

Section: Family Patient Gene(s) Genomic Variation Protein Effect Varimentioning

confidence: 99%

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Johnson¹,

Lowe²,

Fütterer³

et al. 2016

Haematologica

123

135

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“…However specific deletion of Srf in the MK compartment using a PF4-Cre system leads to macrothrombocytopenia with accumulation of abnormal low ploidy early MK progenitors. Mkl1 knockout mice also display thrombocytopenia [160,163] although with a phenotype that is less severe than the one observed in Srf knockout mice, probably relating to a compensating role of Mkl2 [164].…”

Section: Srf and Mkl1mentioning

confidence: 99%

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

Tijssen

Moreau

Ghevaert

2016

Molecular and Cellular Biology of Platelet Formation

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It is now common knowledge that specific repertoires of transcription factors (TFs) determine a cell's protein content and thereby its phenotype. The expression of a given TF is not necessarily cell specific, and many TFs play a pivotal role in several different cell types. For example, TAL1, FLI1, RUNX1, ERG and GATA2 are important regulators of stem cells, but also play a vital role in megakaryopoiesis. Although the megakaryocyte (MK) and its closest relative, the red blood cell, share key TFs like GATA1 and NFE2, the bifurcation between the two lineages has been associated with pairs of TFs that act as a toggle switch (such as FLI1 and KLF1). This chapter will summarise the current knowledge of key transcriptional regulators of MK differentiation and how some of these TFs, despite being expressed in several cell types, can impose MK cell identity. Since the discovery of TPO in 1994, our knowledge of MK biology and differentiation has increased exponentially, but we still lack a deep understanding of what triggers the transition from MK growth and maturation to proplatelet formation. We describe how some well-known TFs control the expression of proteins that play a pivotal role in the dramatic cytoplasmic and cytoskeletal events that accompany proplatelet formation. Finally, we show how TFs can be harnessed in a powerful way to produce MKs and, potentially, platelets in vitro for future clinical applications.

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MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation

Cited by 54 publications

References 46 publications

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects

Transcriptional Regulation of Platelet Formation: Harnessing the Complexity for Efficient Platelet Production In Vitro

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