CKIP-1 regulates mammalian and zebrafish myoblast fusion

Equipe Différenciation Neuromusculaire, Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5239/ENS Lyon, Université de Lyon, IFR128 Biosciences Lyon-Gerland, 46 Allée d'Italie, 69364 LYON cedex 07, France.
Journal of Cell Science (Impact Factor: 5.43). 05/2012; 125(Pt 16):3790-800. DOI: 10.1242/jcs.101048
Source: PubMed


Multinucleated muscle fibres arise by fusion of precursor cells called myoblasts. We previously showed that CKIP-1 ectopic expression in C2C12 myoblasts increased cell fusion. In this work, we report that CKIP-1 depletion drastically impairs C2C12 myoblast fusion in vitro and in vivo during zebrafish muscle development. Within developing fast-twich myotome, Ckip-1 localises at the periphery of fast precursor cells, closed to the plasma membrane. Unlike wild-type myoblasts that form spatially arrayed multinucleated fast myofibres, Ckip-1-deficient myoblasts show a drastic reduction in fusion capacity. A search for CKIP-1 binding partners identified the ARPC1 subunit of Arp2/3 actin nucleation complex essential for myoblast fusion. We demonstrate that CKIP-1, through binding to plasma membrane phosphoinositides via its PH domain, regulates cell morphology and lamellipodia formation by recruiting the Arp2/3 complex at the plasma membrane. These results establish CKIP-1 as a regulator of cortical actin that recruits the Arp2/3 complex at the plasma membrane essential for muscle precursor elongation and fusion.

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    • "A recent study showed that CKIP-1 depletion drastically impaired myoblast fusion in vitro as well as zebrafish muscle development in vivo (Baas et al., 2012), suggesting a positive role of CKIP-1 in myoblast fusion. Briefly, CKIP-1 increased myoblast fusion through its interaction with the Arp2/3 complex at the plasma membrane, which is important for the regulation of cell morphology and lamellipodia formation (Baas et al., 2012). We also found that CKIP-1-deficient mice exhibited spontaneous cardiac hypertrophy with age and were hypersensitive to pressure overload-induced pathological cardiac hypertrophy (Ling et al., 2012). "
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    ABSTRACT: Mesenchymal stem cells (MSCs) are considered as the developmental origin of multiple lineage cells including osteocytes, adipocytes, and muscle cells. Previous studies demonstrated that the PH domain-containing protein CKIP-1 plays an important role in the development of osteoblasts and cardiomyocytes. However, whether CKIP-1 is involved in the generation of adipocytes as well as the MSC differentiation remains unknown. Here we show that CKIP-1 is a novel regulator of MSCs differentiating into adipocytes. MSCs derived from CKIP-1-deficient mice display enhanced adipogenesis upon induction. Further analysis showed that CKIP-1 interacts with the histone deacetylase HDAC1 in the nucleus and inhibits the transcription of CCAAT/enhancer-binding protein α (C/EBPα), which is a crucial adipogenic transcription factor. Ectopic expression of CKIP-1 in a MSC-like cell line C3H/10T1/2 reduced the generation of adipocytes due to suppression of adipogenic factors, including C/EBPα. Moreover, CKIP-1-deficient mice showed an increase in body weight and white adipose tissue gains when fed on a high-fat diet. Collectively, these results suggest that CKIP-1 is a novel inhibitor of MSC-originated adipogenesis by enhancing HDAC1-associated repression of C/EBPα.
    Full-text · Article · Sep 2014 · Journal of Molecular Cell Biology
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    • "The dependence of the effects of Crk and Crkl on the upstream receptors has not been analysed. The Casein kinase 2 interacting protein-1 (CKIP-1) has also been implicated in zebrafish muscle fusion (Baas et al., 2012). "
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    ABSTRACT: Vertebrate skeletal muscle is composed of distinct types of fibre that are functionally adapted through differences in their physiological and metabolic properties. An understanding of the molecular basis of fibre-type specification is of relevance to human health and fitness. The zebrafish provides an attractive model for investigating fibre type specification; not only are their rapidly developing embryos optically transparent, but in contrast to amniotes, the embryonic myotome shows a discrete temporal and spatial separation of fibre type ontogeny that simplifies its analysis. Here we review the current state of understanding of muscle fibre type specification and differentiation during embryonic development of the zebrafish, with a particular focus on the roles of the Prdm1a and Sox6 transcription factors, and consider the relevance of these findings to higher vertebrate muscle biology.
    Full-text · Article · Jun 2013 · Mechanisms of development
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    ABSTRACT: Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent studies provide new insights into how CP and barbed-end capping are regulated. Filament elongation factors, such as formins and ENA/VASP (enabled/vasodilator-stimulated phosphoprotein), indirectly regulate CP by competing with CP for binding to the barbed end, whereas other molecules, including V-1 and phospholipids, directly bind to CP and sterically block its interaction with the filament. In addition, a diverse and unrelated group of proteins interact with CP through a conserved 'capping protein interaction' (CPI) motif. These proteins, including CARMIL (capping protein, ARP2/3 and myosin I linker), CD2AP (CD2-associated protein) and the WASH (WASP and SCAR homologue) complex subunit FAM21, recruit CP to specific subcellular locations and modulate its actin-capping activity via allosteric effects.
    Preview · Article · Sep 2014 · Nature Reviews Molecular Cell Biology
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