Disease relevance of Dag1

• We found that a transient ischemia resulted in a greater damage in the GCL of mice lacking Dp71 than in wt mice [1].
• Transgenic overexpression of dystroglycan does not inhibit muscular dystrophy in mdx mice [2].
• Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy [3].
• Striated muscle-specific disruption of the dystroglycan (DAG1) gene results in loss of the dystrophin-glycoprotein complex in differentiated muscle and a remarkably mild muscular dystrophy with hypertrophy and without tissue fibrosis [4].
• Thus, maintenance of regenerative capacity by satellite cells expressing dystroglycan is likely responsible for mild disease progression in mice and possibly humans [4].
• Astrocyte adhesion to basal lamina proteins was managed in part by alpha-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro [5].

Psychiatry related information on Dag1

• We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci [6].
• Pretreatment with DG (50, 100 and 200 mg/kg p.o.) for seven successive days significantly improved learning and memory in mice and reversed the amnesia induced by both, scopolamine (0.4 mg/kg, i.p.) and natural ageing [7].

High impact information on Dag1

• Reduced ligand binding activity of alpha-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies [8].
• Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required [8].
• Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration [4].
• We demonstrate a similar phenomenon of reexpression of functional dystroglycan in regenerating muscle fibers in a mild form of human muscular dystrophy caused by disruption of posttranslational dystroglycan processing [4].
• We speculate that abnormal post-translational modification of alpha-dystroglycan may contribute to the myd phenotype [9].

Chemical compound and disease context of Dag1

• Thus, the absence of dystrophin may lead to the loss of a dystrophin-associated glycoprotein, and the reduction in this glycoprotein may be one of the first stages of the molecular pathogenesis of muscular dystrophy [10].
• Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, beta-dystroglycan, and alpha-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy [11].
• We found that the COOH-terminal region of alpha-DG's first globular domain and the NH2-terminal region of the mucin-related structures of alpha-DG together form the binding site for LCMV [12].
• Through pioglitazone treatment, gene expression of ephrin B2, Pod-1, actinin 4alpha, and DG1, as well as that of oxidative stress and lipid metabolism, was restored concomitant with attenuation of albuminuria [13].
• The results indicate that LG-I, LG-II, FF and TZ potentially possess tumor initiating activity, while HMF, GL, MGL and DG do not, as judged by the statistical analysis based on the incidences and development of the skin papillomas and/or carcinomas [14].

Biological context of Dag1

• Dystroglycan: brain localisation and chromosome mapping in the mouse [15].
• Comparison of the scotopic electroretinograms (ERG) between Dp71-null mice and wild-type (wt) littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics [1].
• We have investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology [1].
• beta-Dystroglycan is a ubiquitously expressed integral membrane protein that undergoes tyrosine phosphorylation in an adhesion-dependent manner [16].
• We have previously shown that the N-terminal region of beta-dystroglycan, beta-DG(654-750), binds to the C-terminal region of murine alpha-dystroglycan independently from glycosylation [17].

Anatomical context of Dag1

• Overall, the pattern of Drp2 expression corresponds to a subset of the brain regions known to express Dag1, and shows substantial overlap with regions that express various isoforms of dystrophin (particularly in the cerebral cortex, hippocampus and cerebellum) [18].
• Dp71 was associated with the sarcolemma membrane, where it restored normal expression and localization of all members of the dystrophin-associated glycoprotein complex [19].
• Dystroglycan-dystrophin complexes are believed to have structural and signaling functions by linking extracellular matrix proteins to the cytoskeleton and cortical signaling molecules [20].
• Here we characterize a dystroglycan-dystrophin-related protein 2 (DRP2) complex at the surface of myelin-forming Schwann cells [20].
• Hence, the DRP2-dystroglycan complex likely has a distinct function in the terminal stages of PNS myelinogenesis, possibly in the regulation of myelin thickness [20].

Associations of Dag1 with chemical compounds

• We also examined alternative mechanisms of cell-extracellular matrix attachment to elucidate how the muscle basement membrane may subsist in the absence of dystroglycan, and we found the alpha(7B) splice variant of the alpha(7) integrin receptor subunit to be up-regulated [21].
• In addition, the percentage of centrally located myofiber nuclei and the level of serum creatine kinase activity were not decreased in DG/mdx mice relative to mdx animals [2].
• Selective reduction in the nicotinic acetylcholine receptor and dystroglycan at the postsynaptic apparatus of mdx mouse superior cervical ganglion [22].
• Here, we generated a novel monoclonal antibody probe that recognizes only tyrosine 892 phosphorylated beta-dystroglycan (pY892) [16].
• We have shown also that utrophin and beta-dystroglycan co-localise at or near the plasma membrane and that they co-sediment in large complexes on sucrose density gradients [23].

Physical interactions of Dag1

• Therefore, dystroglycan overexpression does not cause the concomitant overexpression of a utrophin-glycoprotein complex in mdx muscles and has no effect on the development of muscle pathology associated with muscular dystrophy [2].
• Blot overlay assays have shown that perlecan binds alpha-DG in a calcium and heparin-sensitive manner [24].
• Disruption of the DRP2-dystroglycan complex is followed by hypermyelination and destabilization of the Schwann cell-axon unit in Prx(-/-) mice [20].
• Biochemical analysis demonstrates that the 120 kDa peripheral nerve alpha-dystroglycan binds merosin as well as laminin [25].
• In S27 cells, which do not aggregate AChRs spontaneously, agrin and laminin binding to dystroglycan-alpha are dramatically decreased [26].

Enzymatic interactions of Dag1

• Our results highlight the potential participation of the short utrophin isoform and the cleaved form of beta-dystroglycan in mdx Schwann cell membrane architecture [27].

Co-localisations of Dag1

• In Xenopus muscle cells, the cell-surface perlecan is precisely colocalized with DG [24].
• Confocal examination showed that alpha-dystroglycan colocalized with agrin in forming the immunological synapse [28].
• The cellular prion protein colocalizes with the dystroglycan complex in the brain [29].

Regulatory relationships of Dag1

• G-utrophin is expressed in brain sites generally different from the regions expressing beta-dystroglycan [30].
• In this regard, interaction of caveolin-3 with beta-dystroglycan may competitively regulate the recruitment of dystrophin to the sarcolemma [31].
• Both perlecan and DG are clustered at ACh receptor clusters induced by spinal neurons or by beads coated with HB-GAM, a heparin-binding growth factor [24].
• Dystroglycan is a widely expressed extracellular matrix receptor that plays a critical role in basement membrane formation, epithelial development, and synaptogenesis [32].
• Down-regulation of alpha-dystroglycan expression inhibited lymphocyte activation even in the presence of agrin [28].

Other interactions of Dag1

• Targeted inactivation of dystrophin gene product Dp71: phenotypic impact in mouse retina [1].
• Furthermore, perlecan is present in muscle lysate immunoprecipitated with an anti-DG antibody [24].
• In contrast, utrophin is a specific component of intercalated disks together with beta- and gamma-sarcoglycans, while beta-dystroglycan, alpha- and delta-sarcoglycans are not present [33].
• Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members [31].
• We report that syntrophin and neuronal nitric-oxide synthase are depleted in muscle fibers lacking both dystrophin and dystroglycan [21].

Analytical, diagnostic and therapeutic context of Dag1

• Moreover, antibodies against dystroglycan can perturb epithelial cell development in kidney organ culture [34].
• These data indicate that the absence of Dp427 at the intraganglionic postsynaptic apparatus of mdx mouse SCG interferes with the presence of both dystroglycan and nAChR clusters at these sites and affects the rate of synapse disassembly induced by postganglionic nerve crush [22].
• Electron microscopy revealed that alpha-dystroglycan immunoreactivity was preferentially associated with the postsynaptic specializations [35].
• On western blot, the antibodies recognized specifically alpha-dystroglycan in cerebellar extracts [35].
• In situ hybridization identifies two neuronal populations, photoreceptors and retinal ganglion cells, that express DG mRNA [36].

References