Distribution of alpha-dystroglycan during embryonic nerve-muscle synaptogenesis.

Cohen, Maxime C.; Jacobson, Christian; Godfrey, Earl W.; Campbell, Kevin P.; Carbonetto, Salvatore

doi:10.1083/jcb.129.4.1093

Cited by 68 publications

(67 citation statements)

References 53 publications

(86 reference statements)

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“…24,25 After 24 hours, the percentage of late apoptotic F4/80 ϩ cells was evaluated by flow cytometry. This experiment showed that the antibody-mediated blocking of agrin-␣-DG interactions enhanced apoptosis ( Figure 6A) and that this effect required agrin expression, because the antibody failed to enhance apoptosis in splenocyte cultures obtained from agrindeficient mice ( Figure 6A).…”

Section: Agrin Delivers Survival Signals Through the ␣-Dg Receptormentioning

confidence: 99%

Agrin is required for survival and function of monocytic cells

Mazzon¹,

Anselmo²,

Soldani³

et al. 2012

Blood

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IntroductionAgrin is an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), which are key molecules involved in skeletal development, hematopoiesis, and inflammation, 1,2 as well as in leukocyte adhesion and motility. 3 Agrin has been extensively studied in the context of the neuromuscular junction (NMJ), where the protein exerts a key role as regulator of postsynaptic differentiation. 4 However, although agrin is broadly expressed during development, 5,6 little is known approximately its role at sites other than the NMJ. In the context of leukocytes, a previous study suggested that agrin may be a regulator of the T-cell immunologic synapse, where it may act as a costimulatory molecule by recruiting lipid rafts. 7 More recently it was reported by our group that agrin deficiency on bone marrow (BM) stroma leads to a defect in CD34 ϩ CD135 Ϫ LSK cell differentiation resulting in reduced cell numbers of all hematopoietic cell lineages. 8 Our studies, as well as previous ones, indicated that the agrin receptor in hematopoietic cells is ␣-dystroglycan (␣-DG), a broadly expressed cell-surface receptor with high affinity for extracellular matrix (ECM) proteins. 9 Although both agrin and ␣-DG are expressed in mature hematopoietic cells, 7,10 the in vivo functional significance of their expression is still unclear. The aim of this study was to analyze the involvement of agrin in leukocyte biology. By using mice that are null for agrin, 11 we demonstrate that agrin is a critical player in the development and function of monocytes and macrophages. Methods MiceAgrin-deficient mice have been described elsewhere. 11 Musk-LAgrn Ϫ/ϩ mice (on C57BL/6 background) were bred at the animal facility of the Humanitas Clinical Institute. Mutant and control mice were genotyped by polymerase chain reaction (PCR) of tail DNA as already described. 11 Congenic B6(CD45.1) mice, purchased from Jackson ImmunoResearch Laboratories, were maintained in the Charles River animal facility and used as recipients of BM transplantation experiments. Procedures involving animals and their care conformed to institutional guidelines in compliance with national (4D.L. N.116, G.U., suppl. 40, 18-2-1992) and international (EEC Council Directive 86/609, OJ L 358,1,12-12-1987; National Institutes of Health Guide for the Care and Use of Laboratory Animals) law and policies. All efforts were made to minimize the number of animals used and their suffering. BM transfer assaysFor BM transfer experiment 1 ϫ 10 6 BM cells from P5 Musk-LAgrn Ϫ/Ϫ or control mice were transferred into 8-to 12-week-old B6(CD45.1) recipients, that were placed under antibiotic treatment 1 week before and 2 weeks after irradiation (950 cGy). Mice were killed and analyzed 9 weeks after transfer; a second BM transfer was performed as the first and analyzed 9 weeks later. HistologyTissues were fixed in 4% (weight/volume) formalin, embedded in paraffin, sectioned, and stained with H&E. Immunohistochemistry and immunofluorescenceSections (5...

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Section: Agrin Delivers Survival Signals Through the ␣-Dg Receptormentioning

confidence: 99%

Agrin is required for survival and function of monocytic cells

Mazzon¹,

Anselmo²,

Soldani³

et al. 2012

Blood

View full text Add to dashboard Cite

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“…MuSK aggregates and co-localizes with AChRs [Fuhrer et al, 1997], is required for neuromuscular synapse formation and in the adult is found only at neuromuscular synapses [Valenzuela et al, 1995]. Another molecule that aggregates and colocalizes with AChRs is ·-dystroglycan [Campanelli et al, 1994;Sugiyama et al, 1994;Apel et al, 1995;Cohen et al, 1995], which is necessary for the stabilization of AChR clusters at neuromuscular synapses [Jacobson et al, 2001]. The interaction of ·-dystroglycan with the extracellular matrix molecule laminin appears to be cru-cial for linking extracellular components to the intracellular actin cytoskeleton in vivo [Ervasti and Campbell, 1993; reviewed by Campbell, 1995].…”

Section: Introductionmentioning

confidence: 99%

Reduced Glycosaminoglycan Sulfation Diminishes the Agrin Signal Transduction Pathway

McDonnell

Grow²

2004

Dev Neurosci

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Proteoglycans consist of a protein core complexed to glycosaminoglycan (GAG) side chains, are abundant in skeletal muscle cell membranes and basal lamina, and have important functions in neuromuscular synapse development. Treatment with chlorate results in the undersulfation of heparan sulfate and chondroitin sulfate GAGs in cell culture. In addition, chlorate treatment decreases the frequency of spontaneous acetylcholine receptor (AChR) clustering in skeletal muscle cell culture. AChRs and other molecules cluster to form the postsynaptic component of neuromuscular synapses. Chlorate treatment is shown here to decrease the frequency of agrin-induced AChR clustering and agrin-induced tyrosine phosphorylation of the AChR β-subunit. These data suggest that reduced GAG chain sulfation decreases the frequency of AChR clustering by diminishing the agrin signal transduction pathway.

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“…Homologs have been identified in a range of organisms including mammals (Ibraghimov-Beskrovnaya et al, 1992), chicken (Brancaccio et al, 1995), zebrafish (Parsons et al, 2002), Xenopus (Cohen et al, 1995), Drosophila (Greener and Roberts, 2000), and nematodes (Grisoni et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies

et al. 2005

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The Large myd mouse has a loss-of-function mutation in the putative glycosyltransferase gene Large. Mutations in the human homolog (LARGE) have been described in a form of congenital muscular dystrophy (MDC1D). Other genes (POMT1, POMGnT1, fukutin, and FKRP) that encode known or putative glycosylation enzymes are also causally associated with human congenital muscular dystrophies. All these diseases are associated with hypoglycosylation of the membrane protein ␣-dystroglycan (␣-DG) and consequent loss of extracellular ligand binding. Hence, they are termed dystroglycanopathies. A paralogous gene for LARGE (LARGE2 or GYLTL1B) may also have a role in DG glycosylation. Using database interrogation and reverse-transcriptase polymerase chain reaction (RT-PCR), we identified vertebrate orthologs of each of these LARGE genes in many vertebrates, including human, mouse, dog, chicken, zebrafish, and pufferfish. However, within invertebrate genomes, we were able to identify only single homologs. We suggest that vertebrate LARGE orthologs be referred to as LARGE1. RT-PCR, dot-blot, and northern analysis indicated that LARGE2 has a more restricted tissue-expression profile than LARGE1. Using epitope-tagged proteins, we show that both LARGE1 and LARGE2 localize to the Golgi apparatus. The high similarity between the LARGE paralogs suggests that LARGE2 may also act on DG. Overexpression of LARGE2 in mouse C2C12 myoblasts results in increased glycosylation of ␣-DG accompanied by an increase in laminin binding. Thus, there may be functional redundancy between LARGE1 and LARGE2. Consistent with this idea, we show that ␣-DG is still fully glycosylated in kidney (a tissue that expresses a high level of LARGE2 mRNA) of Large myd mutant mice.

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Distribution of alpha-dystroglycan during embryonic nerve-muscle synaptogenesis.

Cited by 68 publications

References 53 publications

Agrin is required for survival and function of monocytic cells

Agrin is required for survival and function of monocytic cells

Reduced Glycosaminoglycan Sulfation Diminishes the Agrin Signal Transduction Pathway

Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies

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