Disease relevance of Dag1

• alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies [1].
• Dysfunction of the dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary neuromuscular diseases, including Duchenne muscular dystrophy, Fukuyama-type congenital muscular dystrophy and sarcoglycanopathy (LGMD2C, -D, -E and -F) [2].
• In the present study, we characterized the role of dystroglycan in the adhesion of schwannoma cells to laminin-1 [3].
• Dystroglycan expression in hepatic stellate cells: role in liver fibrosis [4].
• Although defects of the dystroglycan gene have not been identified as the primary causes of hereditary diseases in humans, secondary but significant abnormalities of the dystroglycan complex have been revealed in severe muscular dystrophies, including sarcoglycanopathy (LGMD2C, D, E and F) [5].

High impact information on Dag1

• Defects in myelination coincided with the down-regulation of dystroglycan expression and disruption of the laminin-2 organization and basal lamina assembly on Schwann cell-axon units [6].
• Our results indicate that the processing of beta-dystroglycan by MMP causes the disruption of the link between the ECM and cell membrane via the dystroglycan complex, which could have profound effects on cell viability [2].
• To begin to clarify the pathway by which the dysfunction of the dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the dystroglycan complex in this study [2].
• In the present study, we found mRNA expression for agrin, dystroglycan, and utrophin in kidney cortex, isolated glomeruli, and cultured podocytes and mesangial cells [7].
• Immunoelectron microscopy showed a different distribution pattern as compared to the normal kidney, with segmentally enhanced expression of dystroglycan at the basal side of the extensively fused podocyte foot processes [7].

Biological context of Dag1

• In both experimental diseases, aggregation and reduced density of alpha-dystroglycan by endocytosis by podocytes was observed [8].
• Both means of inhibition of dystroglycan function led to a significant decrease in the ability of laminin-1 to stimulate cell migration [9].
• As an alternative means of inhibition, we used heparin to mask the dystroglycan binding site of the laminin-1, known to overlap with heparin binding sites [9].
• Altogether, these results support a role for dystroglycan as a major cell adhesion molecule in the surface membrane of RT4 cells [3].
• Laminin-6 assembles into multimolecular fibrillar complexes with perlecan and participates in mechanical-signal transduction via a dystroglycan-dependent, integrin-independent mechanism [10].

Anatomical context of Dag1

• Podocyte flattening and disorder of glomerular basement membrane are associated with splitting of dystroglycan-matrix interaction [8].
• In intact rat thyroid glands, antibodies against the alpha (extracellular, laminin-binding subunit) and beta (cytoplasmic/membrane bound) portions of the dystroglycan protein reacted at basolateral membranes where they colocalized with laminin [11].
• We conclude that dystroglycan is present in rat thyroid and in FRTL5 rat thyroid cells and that TSH reduces its expression [11].
• Dystroglycan is involved in laminin-1-stimulated motility of Müller glial cells: combined velocity and directionality analysis [9].
• Immunochemical analysis demonstrated that the dystroglycan complex, comprised of alpha- and beta-dystroglycan, was a major laminin-binding protein complex in the surface membrane of rat schwannoma cell line RT4 [3].

Associations of Dag1 with chemical compounds

• The redistribution of dystroglycan in two experimental rat models of foot process flattening and proteinuria-i.e., podocyte damage induced by polycationic protamine sulfate perfusion, and reactive oxygen species (ROS)-associated puromycin aminonucleoside nephrosis-was examined [8].
• Dystroglycan is a high affinity laminin-binding glycoprotein originally described as a member of the dystrophin-associated glycoprotein complex in muscle [11].
• In adriamycin nephropathy, a decrease in the glomerular capillary wall staining for dystroglycan was observed probably secondary to the extensive fusion of foot processes [7].
• Tryptic peptide mapping of both subunits and amino-terminal sequencing of Torpedo beta-dystroglycan indicate a single cleavage site, corresponding to serine 654 of the mammalian dystroglycan precursor [12].
• Dystroglycan (DG) is part of a multiprotein complex that links the extracellular matrix to the actin cytoskeleton of muscle fibers and that is involved in aggregating acetylcholine receptors at the neuromuscular junction [13].

Physical interactions of Dag1

• Thus, the present results also support the hypothesis that dystrophin interacts with dystroglycan in cerebellar Purkinje neurons [14].

Other interactions of Dag1

• In in vitro solid-phase binding assays, protamine and ROS competed with the binding of alpha-dystroglycan with purified laminin and a recombinant C-terminal fragment of agrin that contains the dystroglycan-binding domain [8].
• Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes [13].
• Dystrophin, utrophin and dystroglycan are present not only in muscle but also in brain [15].
• After Northern blot validation of the results, only three genes appeared upregulated (caveolin-2, the alpha-1 chain of haemoglobin and rat mammary tumor-7) and two downregulated (adiponectin and dystroglycan) [16].
• alpha-dystroglycan is a cell surface receptor that is expressed in many tissues including the nervous system [17].

Analytical, diagnostic and therapeutic context of Dag1

• Immunofluorescence of FRTL-5 cells in the absence of TSH showed a colocalization of dystroglycan and laminin [11].
• We have demonstrated the presence of dystroglycan in the thyroid using immunocytochemistry, immunoblots, ligand binding assays, and relative quantitative RT-PCR [11].
• Furthermore, co-immunoprecipitations between alpha-dystroglycan and beta1-integrin from PC12 cell surfaces suggested complex interactions between neuronal dystroglycan, integrins, and the ECM that induce neurite extension in vitro [17].
• We have previously shown that intraganglionic synapse disassembly consequent on superior cervical ganglion (SCG) neuron axotomy was preceded by the loss of the dystroglycan beta subunit (beta-DG) localized at the postsynaptic specializations [18].
• In Western blot, the antibody was able to detect a number of partially glycosylated alpha-DG isoforms from rat brain and chicken skeletal muscle tissue samples [19].

References