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Gene Review

Agrn  -  agrin

Mus musculus

Synonyms: Agrin, NMF380, nmf380
 
 
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Disease relevance of Agrn

  • An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy [1].
  • We find that both full-length agrin and the C-terminal 95 kDa of agrin (agrin c95), which is sufficient to induce postsynaptic differentiation, are adhesive for chick ciliary ganglion (CG) and forebrain neurons [2].
  • Myasthenia gravis can be induced in mice by injecting the extracellular domain of rat muscle-specific kinase (MuSK), a transmembrane receptor tyrosine kinase involved in agrin signaling at the neuromuscular junction [3].
 

High impact information on Agrn

  • Here we demonstrate that agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component [4].
  • The protein agrin, originally isolated from the basal lamina of the synaptic cleft, is synthesized and secreted by motoneurons and triggers formation of AChR clusters on cultured myotubes [5].
  • In addition, we show that intramuscular nerve branching and presynaptic differentiation are abnormal in the mutant, phenotypes which may reflect either a distinct effect of agrin or impaired retrograde signaling from a defective postsynaptic apparatus [5].
  • Agrin is a nerve-derived factor that can induced molecular reorganizations at the motor endplate, but the mechanism of action of agrin remains poorly understood [4].
  • In S27 cells, which do not aggregate AChRs spontaneously, agrin and laminin binding to dystroglycan-alpha are dramatically decreased [6].
 

Biological context of Agrn

 

Anatomical context of Agrn

 

Associations of Agrn with chemical compounds

  • Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex [12].
  • To elucidate this signaling mechanism, we examined tyrosine phosphorylation of AChR-associated proteins, particularly addressing whether agrin activates Src family kinases bound to the AChR [7].
  • Agrin is a heparan sulfate proteoglycan that is required for the development of postsynaptic specializations at the neuromuscular junction [14].
  • In the current report we show that an NH2-terminal fragment of agrin containing these 130 amino acids is sufficient to bind to Matrigel and that the binding to this preparation is mediated by laminin-1 [15].
  • Here we demonstrate that the murine agrin gene generates two proteins with different NH(2) termini, and present evidence that these isoforms differ in subcellular localization, tissue distribution, and function [16].
 

Physical interactions of Agrn

 

Enzymatic interactions of Agrn

 

Co-localisations of Agrn

  • Confocal examination showed that alpha-dystroglycan colocalized with agrin in forming the immunological synapse [8].
  • These two proteins are also coordinately regulated on the surfaces of cultured myotubes where MuSK and AChRs colocalize both in spontaneous and agrin-induced clusters [18].
 

Regulatory relationships of Agrn

  • During neuromuscular synaptogenesis, neurally released agrin induces aggregation and tyrosine phosphorylation of acetylcholine receptors (AChRs) by acting through both the receptor tyrosine kinase MuSK (muscle-specific kinase) and the AChR-associated protein, rapsyn [7].
  • Down-regulation of alpha-dystroglycan expression inhibited lymphocyte activation even in the presence of agrin [8].
  • Furthermore, this increase in transcriptional activity in response to agrin resulted from a greater number of myonuclei expressing the 1.3-kilobase pair utrophin promoter-nlsLacZ construct [20].
  • Genetic elimination of Cdk5 or blocking ACh production prevents the dispersion of AChR clusters in agrin mutants [21].
  • This temporal pattern of agrin-induced Rac and Rho activation reflects their respective roles in AChR cluster formation [22].
 

Other interactions of Agrn

  • The C-terminus of its core protein contains three globular domain modules which are also found in laminin and agrin, two proteins that bind to dystroglycan (DG, cranin) on the muscle surface with these modules [23].
  • Overexpression of a miniaturized form of this agrin isoform ameliorates the severe muscle dystrophy of laminin alpha2-deficient mice, a mouse model for merosin-deficient congenital muscle dystrophy [14].
  • We also determined the map position of the agrin gene, Agrn, on Chr 4, and on this basis eliminated it as a candidate for scm [24].
  • It is well established that agrin, an extracellular matrix protein, plays a crucial role in the formation of neuromuscular junctions [8].
  • Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism [20].
 

Analytical, diagnostic and therapeutic context of Agrn

  • We used surgical chimeras, isoform-specific mutant mice, and nerve-muscle cocultures to determine the origins and nature of the agrin required for synaptogenesis [10].
  • We have investigated the interactions between the AChR and these proteins in cultured C2 myotubes before and after treatment with agrin, a nerve-derived protein that induces AChRs to cluster [25].
  • Immunoprecipitation experiments showed that MuSK is associated with the AChR and that this association is increased by agrin treatment [26].
  • Western blots confirmed the immunocytochemical data, showing maximum expression of agrin occurs during the early to medium stages of brain development [27].
  • Thus, while agrin will remain bound to synaptic basal lamina for months following denervation, it is removed within days following synaptic retraction [28].

References

  1. An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Moll, J., Barzaghi, P., Lin, S., Bezakova, G., Lochmüller, H., Engvall, E., Müller, U., Ruegg, M.A. Nature (2001) [Pubmed]
  2. A neuronal inhibitory domain in the N-terminal half of agrin. Bixby, J.L., Baerwald-De la Torre, K., Wang, C., Rathjen, F.G., Rüegg, M.A. J. Neurobiol. (2002) [Pubmed]
  3. Delayed synapsing muscles are more severely affected in an experimental model of MuSK-induced myasthenia gravis. Xu, K., Jha, S., Hoch, W., Dryer, S.E. Neuroscience (2006) [Pubmed]
  4. Agrin acts via a MuSK receptor complex. Glass, D.J., Bowen, D.C., Stitt, T.N., Radziejewski, C., Bruno, J., Ryan, T.E., Gies, D.R., Shah, S., Mattsson, K., Burden, S.J., DiStefano, P.S., Valenzuela, D.M., DeChiara, T.M., Yancopoulos, G.D. Cell (1996) [Pubmed]
  5. Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Gautam, M., Noakes, P.G., Moscoso, L., Rupp, F., Scheller, R.H., Merlie, J.P., Sanes, J.R. Cell (1996) [Pubmed]
  6. Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Gee, S.H., Montanaro, F., Lindenbaum, M.H., Carbonetto, S. Cell (1994) [Pubmed]
  7. Agrin-induced activation of acetylcholine receptor-bound Src family kinases requires Rapsyn and correlates with acetylcholine receptor clustering. Mittaud, P., Marangi, P.A., Erb-Vögtli, S., Fuhrer, C. J. Biol. Chem. (2001) [Pubmed]
  8. Agrin is involved in lymphocytes activation that is mediated by alpha-dystroglycan. Zhang, J., Wang, Y., Chu, Y., Su, L., Gong, Y., Zhang, R., Xiong, S. FASEB J. (2006) [Pubmed]
  9. Alternative splicing of agrin alters its binding to heparin, dystroglycan, and the putative agrin receptor. Gesemann, M., Cavalli, V., Denzer, A.J., Brancaccio, A., Schumacher, B., Ruegg, M.A. Neuron (1996) [Pubmed]
  10. Alternatively spliced isoforms of nerve- and muscle-derived agrin: their roles at the neuromuscular junction. Burgess, R.W., Nguyen, Q.T., Son, Y.J., Lichtman, J.W., Sanes, J.R. Neuron (1999) [Pubmed]
  11. Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Apel, E.D., Glass, D.J., Moscoso, L.M., Yancopoulos, G.D., Sanes, J.R. Neuron (1997) [Pubmed]
  12. Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex. Apel, E.D., Roberds, S.L., Campbell, K.P., Merlie, J.P. Neuron (1995) [Pubmed]
  13. The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. Jacobson, C., Côté, P.D., Rossi, S.G., Rotundo, R.L., Carbonetto, S. J. Cell Biol. (2001) [Pubmed]
  14. Expression of mouse agrin in normal, denervated and dystrophic muscle. Eusebio, A., Oliveri, F., Barzaghi, P., Ruegg, M.A. Neuromuscul. Disord. (2003) [Pubmed]
  15. Agrin binds to the nerve-muscle basal lamina via laminin. Denzer, A.J., Brandenberger, R., Gesemann, M., Chiquet, M., Ruegg, M.A. J. Cell Biol. (1997) [Pubmed]
  16. Agrin isoforms with distinct amino termini: differential expression, localization, and function. Burgess, R.W., Skarnes, W.C., Sanes, J.R. J. Cell Biol. (2000) [Pubmed]
  17. Non-muscle alpha-dystroglycan is involved in epithelial development. Durbeej, M., Larsson, E., Ibraghimov-Beskrovnaya, O., Roberds, S.L., Campbell, K.P., Ekblom, P. J. Cell Biol. (1995) [Pubmed]
  18. Localization and regulation of MuSK at the neuromuscular junction. Bowen, D.C., Park, J.S., Bodine, S., Stark, J.L., Valenzuela, D.M., Stitt, T.N., Yancopoulos, G.D., Lindsay, R.M., Glass, D.J., DiStefano, P.S. Dev. Biol. (1998) [Pubmed]
  19. Structural alterations at the neuromuscular junctions of matrix metalloproteinase 3 null mutant mice. VanSaun, M., Herrera, A.A., Werle, M.J. J. Neurocytol. (2003) [Pubmed]
  20. Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism. Gramolini, A.O., Burton, E.A., Tinsley, J.M., Ferns, M.J., Cartaud, A., Cartaud, J., Davies, K.E., Lunde, J.A., Jasmin, B.J. J. Biol. Chem. (1998) [Pubmed]
  21. Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E.P., Gage, F.H., Lee, K.F. Neuron (2005) [Pubmed]
  22. Cooperative regulation by Rac and Rho of agrin-induced acetylcholine receptor clustering in muscle cells. Weston, C., Gordon, C., Teressa, G., Hod, E., Ren, X.D., Prives, J. J. Biol. Chem. (2003) [Pubmed]
  23. The relationship between perlecan and dystroglycan and its implication in the formation of the neuromuscular junction. Peng, H.B., Ali, A.A., Daggett, D.F., Rauvala, H., Hassell, J.R., Smalheiser, N.R. Cell Adhes. Commun. (1998) [Pubmed]
  24. Scrambler, a new neurological mutation of the mouse with abnormalities of neuronal migration. Sweet, H.O., Bronson, R.T., Johnson, K.R., Cook, S.A., Davisson, M.T. Mamm. Genome (1996) [Pubmed]
  25. Roles of rapsyn and agrin in interaction of postsynaptic proteins with acetylcholine receptors. Fuhrer, C., Gautam, M., Sugiyama, J.E., Hall, Z.W. J. Neurosci. (1999) [Pubmed]
  26. Association of muscle-specific kinase MuSK with the acetylcholine receptor in mammalian muscle. Fuhrer, C., Sugiyama, J.E., Taylor, R.G., Hall, Z.W. EMBO J. (1997) [Pubmed]
  27. Distribution and substrate properties of agrin, a heparan sulfate proteoglycan of developing axonal pathways. Halfter, W., Schurer, B., Yip, J., Yip, L., Tsen, G., Lee, J.A., Cole, G.J. J. Comp. Neurol. (1997) [Pubmed]
  28. Anti-agrin staining is absent at abandoned synaptic sites of frog neuromuscular junctions. Werle, M.J., Sojka, A.M. J. Neurobiol. (1996) [Pubmed]
 
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