A- and B-utrophin Have Different Expression Patterns and Are Differentially Up-regulated in mdx Muscle

Weir, Andrew; Burton, Edward A.; Harrod, Graham V.; Davies, Kay E.

doi:10.1074/jbc.m205177200

Cited by 117 publications

(124 citation statements)

References 44 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…By using isoform-specific PCR primers and antibodies, we were also able to show that the increased utrophin expression in type I and IIA fibers is due to a greater expression of utrophin A. This particular isoform of utrophin is preferentially expressed at the level of the postsynaptic membrane of the neuromuscular junction (31). It is therefore interesting to note that, under specific conditions, expression of this utrophin isoform extends well into extrasynaptic compartments of muscle fibers.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling

Chakkalakal

Stocksley

Harrison

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

120

139

View full text Add to dashboard Cite

Utrophin levels have recently been shown to be more abundant in slow vs. fast muscles, but the nature of the molecular events underlying this difference remains to be fully elucidated. Here, we determined whether this difference is due to the expression of utrophin A or B, and examined whether transcriptional regulatory mechanisms are also involved. Immunofluorescence experiments revealed that slower fibers contain significantly more utrophin A in extrasynaptic regions as compared with fast fibers. Single-fiber RT-PCR analysis demonstrated that expression of utrophin A transcripts correlates with the oxidative capacity of muscle fibers, with cells expressing myosin heavy chain I and IIa demonstrating the highest levels. Functional muscle overload, which stimulates expression of a slower, more oxidative phenotype, induced a significant increase in utrophin A mRNA levels. Because calcineurin has been implicated in controlling this slower, high oxidative myofiber program, we examined expression of utrophin A transcripts in muscles having altered calcineurin activity. Calcineurin inhibition resulted in an 80% decrease in utrophin A mRNA levels. Conversely, muscles from transgenic mice expressing an active form of calcineurin displayed higher levels of utrophin A transcripts. Electrophoretic mobility shift and supershift assays revealed the presence of a nuclear factor of activated T cells (NFAT) binding site in the utrophin A promoter. Transfection and direct gene transfer studies showed that active forms of calcineurin or nuclear NFATc1 transactivate the utrophin A promoter. Together, these results indicate that expression of utrophin A is related to the oxidative capacity of muscle fibers, and implicate calcineurin and its effector NFAT in this mechanism.

show abstract

Section: Discussionmentioning

confidence: 86%

“…31). We therefore generated a rabbit polyclonal antibody against a specific peptide sequence in the distinct N-terminal region of utrophin A (16).…”

Section: Resultsmentioning

confidence: 99%

Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling

Chakkalakal

Stocksley

Harrison

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

120

139

View full text Add to dashboard Cite

show abstract

“…Although full-length utrophin protein can be generated using independently regulated A (Dennis et al, 1996) and B (Burton et al, 1999) promoters, myofiber utrophin expression is chiefly controlled via the utrophin-A promoter (Weir et al, 2002;Chakkalakal et al, 2003), and it is thus the subject of this investigation. Spatial and temporal expression of utrophin-A at the NMJ parallels that of nicotinic acetylcholine receptor (nACHR) subunits.…”

Section: Introductionmentioning

confidence: 99%

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

Perkins

Basu

Budak

et al. 2007

MBoC

View full text Add to dashboard Cite

Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABP␣/␤ to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest "repressing repressors" as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle. INTRODUCTIONDuchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by gene mutations leading to qualitative or quantitative disturbances in dystrophin expression (Hoffman et al., 1987). Dystrophin-related protein or utrophin is considered the autosomal homologue of dystrophin, because it shares extensive sequence homology as well as its size and abundance in muscle (Love et al., 1989;Khurana et al., 1990;Tinsley et al., 1992). Utrophin and dystrophin also share functional properties such as the ability to associate with the dystroglycan complex and bind F-actin (Matsumura et al., 1992;Winder and Kendrick, 1995;Rybakova et al., 2002). Direct evidence for the ability of utrophin to functionally substitute comes from experiments demonstrating that utrophin overexpression driven either by transgenic means Rafael et al., 1998;Tinsley et al., 1998;Fisher et al., 2001) or viral vectors (Gilbert et al., 1999;Wakefield et al., 2000;Cerletti et al., 2003) can rescue dystrophin-deficient muscle. Despite these functional similarities, dystrophin and utrophin exhibit distinct localization in normal adult tissues.Perinatally, utrophin is expressed throughout the sarcolemma, however, its expression declines as that of dystrophin increases (Khurana et al., 1991;Clerk et al., 1993), leading to its spatially restricted expression at neuromuscular and myotendinous junctions (NMJs and MTJs, respectively) of adult myofibers. These features and relevance toward a therapy for DMD provide a powerful impetus for b...

show abstract

“…Utrophin is a paralogue of dystrophin and has two full-length mRNA species, A and B, which have very different expression patterns. B-utrophin is expressed in vascular endothelial cells, whereas A-utrophin is expressed at the neuromuscular junction, choroid plexus, pia mater, and renal glomerulus (34). TECTA is not expressed in the kidneys, but computer modeling predicts presence of several tectorinlike genes in this region that would need to be studied further.…”

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Progressive Nephropathy with Deafness

Prakash¹,

Chung²,

Sinha³

et al. 2003

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: Ϫ6.1 and Ϫ4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at ϭ 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype.

show abstract

A- and B-utrophin Have Different Expression Patterns and Are Differentially Up-regulated in mdx Muscle

Cited by 117 publications

References 44 publications

Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling

Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling

Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

Autosomal Dominant Progressive Nephropathy with Deafness

Contact Info

Product

Resources

About