Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance

Gurniak, Christine B.; Chevessier, Frédéric; Jokwitz, Melanie; Jönsson, Friederike; Perlas, Emerald; Richter, Hendrik; Matern, Gabi; Boyl, Pietro Pilo; Chaponnier, Christine; Fürst, Dieter O.; Schröder, Rolf; Witke, Walter

doi:10.1016/j.ejcb.2014.01.007

Cited by 55 publications

(66 citation statements)

References 66 publications

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“…Soluble protein concentrations were measured using standard Bradford assay and determined using a microplate reader (Varioskan Flash, Thermo Scientific). Western blotting was done according to standard procedures and using primary antibodies as follows: FMNL2/3 (Abcam; #ab57963; 1:1,000 dilution), GAPDH (Calbiochem; clone 6C5; #CB1001; 1:10,000 dilution), α-Tubulin (Synaptic Systems; clone 3A2; #302117; 1:50,000 dilution), phospho-cofilin (Cell Signaling; #3311; 1:1,000 dilution), cofilin 1 (KG60; kindly provided by Walter Witke; University of Bonn; Germany65; 1:500 dilution), FMNL1 (Abcam; #ab97456; 1:1,000 dilution). Secondary antibodies were purchased from Invitrogen.…”

Section: Methodsmentioning

confidence: 99%

FMNL formins boost lamellipodial force generation

et al. 2017

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Migration frequently involves Rac-mediated protrusion of lamellipodia, formed by Arp2/3 complex-dependent branching thought to be crucial for force generation and stability of these networks. The formins FMNL2 and FMNL3 are Cdc42 effectors targeting to the lamellipodium tip and shown here to nucleate and elongate actin filaments with complementary activities in vitro. In migrating B16-F1 melanoma cells, both formins contribute to the velocity of lamellipodium protrusion. Loss of FMNL2/3 function in melanoma cells and fibroblasts reduces lamellipodial width, actin filament density and -bundling, without changing patterns of Arp2/3 complex incorporation. Strikingly, in melanoma cells, FMNL2/3 gene inactivation almost completely abolishes protrusion forces exerted by lamellipodia and modifies their ultrastructural organization. Consistently, CRISPR/Cas-mediated depletion of FMNL2/3 in fibroblasts reduces both migration and capability of cells to move against viscous media. Together, we conclude that force generation in lamellipodia strongly depends on FMNL formin activity, operating in addition to Arp2/3 complex-dependent filament branching.

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Section: Methodsmentioning

confidence: 99%

FMNL formins boost lamellipodial force generation

et al. 2017

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“…Mutations in the cofilin-2 gene lead to myopathies in humans (Agrawal et al, 2007; Ockeloen et al, 2012), and cofilin-2 deficient mice show progressive disruption of the sarcomeric architecture and abnormal accumulation of F-actin in skeletal muscles. Primary myofibril assembly and muscle development are unaffected in these mice, but postnatal animals display defects in sarcomeric actin exchange and muscle maintenance (Agrawal et al, 2012; Gurniak et al, 2014). Cofilin-2 was reported to partially localize to myofibrils in muscle cells, suggesting that it may be involved in regulation of actin dynamics in sarcomeres (Nakashima et al, 2005; Gurniak et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Primary myofibril assembly and muscle development are unaffected in these mice, but postnatal animals display defects in sarcomeric actin exchange and muscle maintenance (Agrawal et al, 2012; Gurniak et al, 2014). Cofilin-2 was reported to partially localize to myofibrils in muscle cells, suggesting that it may be involved in regulation of actin dynamics in sarcomeres (Nakashima et al, 2005; Gurniak et al, 2014). However, the mechanism by which cofilin-2 contributes to the assembly and/or maintenance of actin filament structures in myofibrils is unknown.…”

Section: Introductionmentioning

confidence: 99%

Cofilin-2 Controls Actin Filament Length in Muscle Sarcomeres

et al. 2014

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SUMMARY ADF/cofilins drive cytoskeletal dynamics by promoting the disassembly of ‘aged’ ADP-actin filaments. Mammals express several ADF/cofilin isoforms, but their specific biochemical activities and cellular functions have not been studied in detail. Here we demonstrate that the muscle-specific isoform cofilin-2 promotes actin filament disassembly in sarcomeres to control the precise length of thin filaments in the contractile apparatus. In contrast to other isoforms, cofilin-2 efficiently binds and disassembles both ADP- and ATP/ADP-Pi-actin filaments. We mapped surface-exposed cofilin-2-specific residues required for ATP-actin binding and propose that these residues function as an ‘actin nucleotide-state sensor’ among ADF/cofilins. The results suggest that cofilin-2 evolved specific biochemical and cellular properties allowing it to control actin dynamics in sarcomeres, where filament pointed ends may contain a mixture of ADP- and ATP/ADP-Pi-actin subunits. Our findings also offer a rationale for why cofilin-2 mutations in humans lead to myopathies.

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“…Genetic deletion of CFL2 in mice causes lethality eight days after birth due to severe muscle deficiencies and aberrant actin accumulation within muscle myofibrils, indicating that CFL2 has an important role in muscle development and maintenance . A role of CFL2 in actin monomer exchange in sarcomeres has also been proposed (Gurniak et al, 2014).…”

Section: Box 1 Physiological Importance Of Adf and Cofilinsmentioning

confidence: 99%

Cellular functions of the ADF/cofilin family at a glance

Kanellos

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2016

Journal of Cell Science

210

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The actin depolymerizing factor (ADF)/cofilin family comprises small actin-binding proteins with crucial roles in development, tissue homeostasis and disease. They are best known for their roles in regulating actin dynamics by promoting actin treadmilling and thereby driving membrane protrusion and cell motility. However, recent discoveries have increased our understanding of the functions of these proteins beyond their well-characterized roles. This Cell Science at a Glance article and the accompanying poster serve as an introduction to the diverse roles of the ADF/cofilin family in cells.The first part of the article summarizes their actions in actin treadmilling and the main mechanisms for their intracellular regulation; the second part aims to provide an outline of the emerging cellular roles attributed to the ADF/cofilin family, besides their actions in actin turnover. The latter part discusses an array of diverse processes, which include regulation of intracellular contractility, maintenance of nuclear integrity, transcriptional regulation, nuclear actin monomer transfer, apoptosis and lipid metabolism. Some of these could, of course, be indirect consequences of actin treadmilling functions, and this is discussed.

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Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance

Cited by 55 publications

References 66 publications

FMNL formins boost lamellipodial force generation

FMNL formins boost lamellipodial force generation

Cofilin-2 Controls Actin Filament Length in Muscle Sarcomeres

Cellular functions of the ADF/cofilin family at a glance

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