Expression and alternative splicing of N‐RAP during mouse skeletal muscle development

Lu, Shajia; Borst, Diane E.; Horowits, Robert

doi:10.1002/cm.20317

Cited by 20 publications

(32 citation statements)

References 37 publications

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“…Overexpression of Klbdc2 in C2C12 myoblasts abolished the ability of the cells to respond to the chemoattractant properties of hepatocyte growth factor, known to be important in myoblast migration (10). In our preliminary studies, we observed upregulation of Krp1 between 24 and 48 h following induction of myoblast differentiation in C2 myoblasts, considerably before myofibril formation and in agreement with previous observations made in differentiating primary human myoblasts (17,22). We therefore decided to investigate the hypothesis that Krp1 might have important functions at earlier stages of myoblast differentiation, such as cell migration and elongation.…”

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confidence: 82%

BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts

Paxton

Cosgrove

Drozd

et al. 2011

American Journal of Physiology-Cell Physiology

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The BTB-Kelch protein Krp1 is highly and specifically expressed in skeletal muscle, where it is proposed to have a role in myofibril formation. We observed significant upregulation of Krp1 in C2 cells early in myoblast differentiation, well before myofibrillogenesis. Krp1 has a role in cytoskeletal organization and cell motility; since myoblast migration and elongation/alignment are important events in early myogenesis, we hypothesized that Krp1 is involved with earlier regulation of differentiation. Krp1 protein levels were detectable by 24 h after induction of differentiation in C2 cells and were significantly upregulated by 48 h, i.e., following the onset myogenin expression and preceding myosin heavy chain (MHC) upregulation. Upregulation of Krp1 required a myogenic stimulus as signaling derived from increased myoblast cell density was insufficient to activate Krp1 expression. Examination of putative Krp1 proximal promoter regions revealed consensus E box elements associated with myogenic basic helix-loop-helix binding. The activity of a luciferase promoter-reporter construct encompassing this 2,000-bp region increased in differentiating C2 myoblasts and in C2 cells transfected with myogenin and/or MyoD. Knockdown of Krp1 via short hairpin RNA resulted in increased C2 cell number and proliferation rate as assessed by bromodeoxyuridine incorporation, whereas overexpression of Krp1-myc had the opposite effect; apoptosis was unchanged. No effects of changed Krp1 protein levels on cell migration were observed, either by scratch wound assay or live cell imaging. Paradoxically, both knockdown and overexpression of Krp1 inhibited myoblast differentiation assessed by expression of myogenin, MEF2C, MHC, and cell fusion.

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supporting

confidence: 82%

BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts

Paxton

Cosgrove

Drozd

et al. 2011

American Journal of Physiology-Cell Physiology

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“…NRAP is expressed in myofibril precursors during myofibrillogenesis 2, 3 . In adult mice and humans NRAP expression is limited to: (i) terminal bundles of actin filaments at the myotendinous junctions of skeletal muscles, and (ii) the intercalated discs of the heart muscles and is not observed in mature sarcomeres 1, 4–6 .…”

Section: Introductionmentioning

confidence: 99%

Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Truszkowska

Bilińska

Muchowicz

et al. 2017

Sci Rep

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The genetic background of dilated cardiomyopathy is highly heterogeneous, with close to 100 known genes and a number of candidates described to date. Nebulin-related-anchoring protein (NRAP) is an actin-binding cytoskeletal protein expressed predominantly in striated and cardiac muscles, and is involved in myofibrillar assembly in the foetal heart and in force transmission in the adult heart. The homozygous NRAP truncating variant (rs201084642), which is predicted to introduce premature stop codon into all NRAP isoforms, was revealed in the dilated cardiomyopathy patient using whole exome sequencing. The same genotype was detected in the asymptomatic proband’s brother. The expression of the NRAP protein was undetectable in the patient’s heart muscle by the Western blot. Genotyping for rs201084642 in the ethnically matched cohort of 231 dilated cardiomyopathy patients did not reveal any additional subjects with this variant. Our findings suggest that the biallelic loss-of-function mutation in NRAP could constitute a relatively rare, low-penetrance genetic risk factor for dilated cardiomyopathy.

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“…16,17,75 In heart, the N-RAP-c isoform is expressed, while in skeletal muscle 2 different isoforms are expressed (N-RAP-s and in lower amounts N-RAP-c). 17, 76 The N-RAP-c isoform is missing nebulin simple repeat 9 compared with the N-RAP-s isoform. N-RAP is expressed from embryonic day 10.5, initially in myofibril precursors and subsequently within the Z-line and M-line of maturing myofibrils.…”

Section: N-rap (Nebulin-related Anchoring Protein)mentioning

confidence: 99%

Roles of Nebulin Family Members in the Heart

Bang

Chen

2015

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp ment. 4,10,11,13-15 N-RAP is the second largest member of the nebulin family (193)(194)(195)(196) kDa in humans) containing 46 nebulin repeats of which 35 are organized into 5 super repeats, 16,17 while nebulette (109 kDa), 3,18 LASP-1 (37 kDa), 19,20 and LASP-2 (34 kDa) 21-23 contain only simple nebulin repeats. Nebulette contains up to 23 repeats, 3 while LASP-1 and LASP-2 contain only 2 and 3 repeats, respectively. Except for N-RAP the family members also share an SH3 domain at their C-terminus, and N-RAP, LASP-1, and LASP-2 contain an N-terminal LIM domain not present in nebulin or nebulette. Apart from their similar domain structure and linkage to actin, the members of the nebulin family are quite heterogeneous both with respect to molecular size (34-900 kDa) and expression pattern as well as function, which includes roles in stabilization and scaffolding of cytoskeletal structures, cell migration, and organization of the actin cytoskeleton. In the present review, we will focus on the roles of nebulin family members in the heart. NebulinMutations in the nebulin gene are causative for nemaline myopathy 24,25 and the function of nebulin in skeletal muscle has been extensively studied both in vitro and in vivo, revealing its multifunctional role in various processes required for efficient myofibrillar force generation, including (1) regulation he nebulin family of actin-binding cytoskeletal proteins comprises nebulin, nebulette, N-RAP (Nebulinrelated anchoring protein), LASP-1 (LIM and Src homology 3 (SH3) Protein-1), and LASP-2 (LIM and SH3 Protein-2/LIM-Nebulette), a splice variant of nebulette. 1 The members of the family contain various numbers of 35-residue nebulin repeats, containing a central conserved SDXXYK consensus motif 2,3 and named after the founding member nebulin, which includes up to 185 copies of the repeat (Figure). 4,5 Nebulin is the largest member of the nebulin family, with a molecular weight ranging from 600 to 900 kDa and expressed predominantly in skeletal muscle, where it stretches along the actin thin filament with its C-terminal region anchored in the sarcomeric Z-line and its N-terminal region extending towards the pointed end of the thin filament. 4,6 For reviews on the sarcomere and the Z-line, see Frank et al 7 and Sheikh et al. 8 Within the central part of nebulin (repeats 9-162), the nebulin repeats are organized into "super repeats" of 7 repeats, containing a conserved WLKGIGW motif at the end of the third repeat of each super repeat. 4 Each nebulin repeat binds to an actin monomer, 9-12 while the nebulin super repeats correspond to the architecture of the thin filament with 1 tropomyosin/ troponin complex for every 7 actin subunits, and interact with troponin T and tropomyosin along the length of the thin fila- Roles of Nebulin Family Members in the HeartMarie-Louise Bang, PhD; Ju Chen, PhDThe members of the nebulin protein family, including nebulin, nebulette, LASP-1, LASP-2, ...

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Expression and alternative splicing of N‐RAP during mouse skeletal muscle development

Cited by 20 publications

References 37 publications

BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts

BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts

Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Roles of Nebulin Family Members in the Heart

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