About this Journal Submit a Manuscript Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 849426, 19 pages
http://dx.doi.org/10.1155/2010/849426
Review Article

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

1Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR8195, Orsay, 91405, France
2CNRS, Orsay, 91405, France

Received 16 December 2009; Accepted 14 March 2010

Academic Editor: Meena Upadhyaya

Copyright © 2010 Caroline Perronnet and Cyrille Vaillend. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. P. Hoffman, R. H. Brown Jr., and L. M. Kunkel, “Dystrophin: the protein product of the Duchenne muscular dystrophy locus,” Cell, vol. 51, no. 6, pp. 919–928, 1987.
  2. V. J. Hinton, B. C. De Vivo, N. E. Nereo, E. Goldstein, and Y. Stern, “Poor verbal working memory across intellectual level in boys with Duchenne dystrophy,” Neurology, vol. 54, no. 11, pp. 2127–2132, 2000.
  3. I. Desguerre, C. Christov, M. Mayer, et al., “Clinical heterogeneity of Duchenne muscular dystrophy (DMD): definition of sub-phenotypes and predictive criteria by long-term follow-up,” PloS One, vol. 4, no. 2, article e4347, 2009. View at Publisher · View at Google Scholar · View at PubMed
  4. D. J. Blake, A. Weir, S. E. Newey, and K. E. Davies, “Function and genetics of dystrophin and dystrophin-related proteins in muscle,” Physiological Reviews, vol. 82, no. 2, pp. 291–329, 2002.
  5. T. Haenggi and J.-M. Fritschy, “Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue,” Cellular and Molecular Life Sciences, vol. 63, no. 14, pp. 1614–1631, 2006. View at Publisher · View at Google Scholar · View at PubMed
  6. G. S. K. Pilgram, S. Potikanond, R. A. Baines, L. G. Fradkin, and J. N. Noordermeer, “The roles of the dystrophin-associated glycoprotein complex at the synapse,” Molecular Neurobiology, vol. 41, no. 1, pp. 1–21, 2010. View at Publisher · View at Google Scholar · View at PubMed
  7. C. Billard, P. Gillet, J. L. Signoret, et al., “Cognitive functions in duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy,” Neuromuscular Disorders, vol. 2, no. 5-6, pp. 371–378, 1992.
  8. S. Cotton, N. J. Voudouris, and K. M. Greenwood, “Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients,” Developmental Medicine and Child Neurology, vol. 43, no. 7, pp. 497–501, 2001.
  9. C. Billard, P. Gillet, M.-A. Barthez, C. Hommet, and P. Bertrand, “Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy,” Developmental Medicine and Child Neurology, vol. 40, no. 1, pp. 12–20, 1998.
  10. M. Roccella, R. Pace, and M. T. De Gregorio, “Psychopathological assessment in children affected by Duchenne de Boulogne muscular dystrophy,” Minerva Pediatrica, vol. 55, no. 3, pp. 267–276, 2003.
  11. V. J. Hinton, D. C. De Vivo, N. E. Nereo, E. Goldstein, and Y. Stern, “Selective deficits in verbal working memory associated with a known genetic etiology: the neuropsychological profile of Duchenne muscular dystrophy,” Journal of the International Neuropsychological Society, vol. 7, no. 1, pp. 45–54, 2001. View at Publisher · View at Google Scholar
  12. J. G. M. Hendriksen and J. S. H. Vles, “Neuropsychiatric disorders in males with duchenne muscular dystrophy: frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive-compulsive disorder,” Journal of Child Neurology, vol. 23, no. 5, pp. 477–481, 2008. View at Publisher · View at Google Scholar · View at PubMed
  13. V. J. Hinton, N. E. Nereo, R. J. Fee, and S. E. Cyrulnik, “Social behavior problems in boys with Duchenne muscular dystrophy,” Journal of Developmental and Behavioral Pediatrics, vol. 27, no. 6, pp. 470–476, 2006. View at Publisher · View at Google Scholar
  14. V. J. Hinton, R. J. Fee, D. C. De Vivo, and E. Goldstein, “Poor facial affect recognition among boys with Duchenne muscular dystrophy,” Journal of Autism and Developmental Disorders, vol. 37, no. 10, pp. 1925–1933, 2007. View at Publisher · View at Google Scholar · View at PubMed
  15. J. Donders and C. Taneja, “Neurobehavioral characteristics of children with duchenne muscular dystrophy,” Child Neuropsychology, vol. 15, no. 3, pp. 295–304, 2009. View at Publisher · View at Google Scholar · View at PubMed
  16. S. E. Cyrulnik and V. J. Hinton, “Duchenne muscular dystrophy: a cerebellar disorder?” Neuroscience and Biobehavioral Reviews, vol. 32, no. 3, pp. 486–496, 2008. View at Publisher · View at Google Scholar · View at PubMed
  17. H. G. W. Lidov, T. J. Byers, and L. M. Kunkel, “The distribution of dystrophin in the murine central nervous system: an immunocytochemical study,” Neuroscience, vol. 54, no. 1, pp. 167–187, 1993. View at Publisher · View at Google Scholar
  18. D. Rapaport, M. R. Passos-Bueno, L. Brandao, D. Love, M. Vainzof, and M. Zatz, “Apparent association of mental retardation and specific patterns of deletions screened with probes cf56a and cf23a in Duchenne Muscular Dystrophy,” American Journal of Medical Genetics, vol. 39, no. 4, pp. 437–441, 1991.
  19. U. Lenk, R. Hanke, H. Thiele, and A. Speer, “Point mutations at the carboxy terminus of the human dystrophin gene: implications for an association with mental retardation in DMD patients,” Human Molecular Genetics, vol. 2, no. 11, pp. 1877–1881, 1993.
  20. M.-P. Moizard, C. Billard, A. Toutain, F. Berret, N. Marmin, and C. Moraine, “Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?” American Journal of Medical Genetics, vol. 80, no. 1, pp. 32–41, 1998. View at Publisher · View at Google Scholar
  21. M.-P. Moizard, A. Toutain, D. Fournier, et al., “Severe cognitive impairment in DMD: obvious clinical indication for Dp71 isoform point mutation screening,” European Journal of Human Genetics, vol. 8, no. 7, pp. 552–556, 2000. View at Publisher · View at Google Scholar · View at PubMed
  22. G. Felisari, F. M. Boneschi, A. Bardoni, et al., “Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy,” Neurology, vol. 55, no. 4, pp. 559–564, 2000.
  23. F. Daoud, N. Angeard, B. Demerre, et al., “Analysis of Dp71 contribution in the severity of mental retardation through comparison of Duchenne and Becker patients differing by mutation consequences on Dp71 expression,” Human Molecular Genetics, vol. 18, no. 20, pp. 3779–3794, 2009. View at Publisher · View at Google Scholar · View at PubMed
  24. P. J. Taylor, G. A. Betts, S. Maroulis, et al., “Dystrophin gene mutation location and the risk of cognitive impairment in duchenne muscular dystrophy,” PloS One, vol. 5, no. 1, article e8803, 2010. View at Publisher · View at Google Scholar · View at PubMed
  25. F. Muntoni, S. Torelli, and A. Ferlini, “Dystrophin and mutations: one gene, several proteins, multiple phenotypes,” Lancet Neurology, vol. 2, no. 12, pp. 731–740, 2003. View at Publisher · View at Google Scholar
  26. L. V. B. Nicholson, M. A. Johnson, K. M. D. Bushby, et al., “Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 1. Trends across the clinical groups,” Journal of Medical Genetics, vol. 30, no. 9, pp. 728–736, 1993.
  27. J. A. Rafael, G. A. Cox, K. Corrado, D. Jung, K. P. Campbell, and J. S. Chamberlain, “Forced expression of dystrophin deletion constructs reveals structure-function correlations,” Journal of Cell Biology, vol. 134, no. 1, pp. 93–102, 1996. View at Publisher · View at Google Scholar
  28. H. M. Sadoulet-Puccio and L. M. Kunkel, “Dystrophin and its isoforms,” Brain Pathology, vol. 6, no. 1, pp. 25–35, 1996.
  29. S. J. Winder, “The membrane-cytoskeleton interface: the role of dystrophin and utrophin,” Journal of Muscle Research and Cell Motility, vol. 18, no. 6, pp. 617–629, 1997.
  30. T. S. Khurana and K. E. Davies, “Pharmacological strategies for muscular dystrophy,” Nature Reviews Drug Discovery, vol. 2, no. 5, pp. 379–390, 2003. View at Publisher · View at Google Scholar · View at PubMed
  31. M. Luise, C. Presotto, L. Senter, et al., “Dystrophin is phosphorylated by endogenous protein kinases,” Biochemical Journal, vol. 293, no. 1, pp. 243–247, 1993.
  32. H. W. Jarrett and J. L. Foster, “Alternate binding of actin and calmodulin to multiple sites on dystrophin,” Journal of Biological Chemistry, vol. 270, no. 10, pp. 5578–5586, 1995. View at Publisher · View at Google Scholar
  33. L. Senter, S. Ceoldo, M. M. Petrusa, and G. Salviati, “Phosphorylation of dystrophin: effects on actin binding,” Biochemical and Biophysical Research Communications, vol. 206, no. 1, pp. 57–63, 1995. View at Publisher · View at Google Scholar · View at PubMed
  34. M. Michalak, S. Y. Fu, R. E. Milner, J. L. Busaan, and J. E. Hance, “Phosphorylation of the carboxyl-terminal region of dystrophin,” Biochemistry and Cell Biology, vol. 74, no. 4, pp. 431–437, 1996.
  35. M. P. Walsh, J. L. Busaan, E. D. Fraser, S. Y. Fu, M. D. Pato, and M. Michalak, “Characterization of the recombinant C-terminal domain of dystrophin: phosphorylation by calmodulin-dependent protein kinase II and dephosphorylation by type 2B protein phosphatase,” Biochemistry, vol. 34, no. 16, pp. 5561–5568, 1995.
  36. T. A. Rando, “The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies,” Muscle and Nerve, vol. 24, no. 12, pp. 1575–1594, 2001. View at Publisher · View at Google Scholar · View at PubMed
  37. C. G. Carlson, “The dystrophinopathies: an alternative to the structural hypothesis,” Neurobiology of Disease, vol. 5, no. 1, pp. 3–15, 1998. View at Publisher · View at Google Scholar · View at PubMed
  38. H. G. W. Lidov, “Dystrophin in the nervous system,” Brain Pathology, vol. 6, no. 1, pp. 63–77, 1996.
  39. I. Knuesel, B. C. Bornhauser, R. A. Zuellig, F. Heller, M. C. Schaub, and J.-M. Fritschy, “Differential expression of utrophin and dystrophin in CNS neurons: an in situ hybridization and immunohistochemical study,” Journal of Comparative Neurology, vol. 422, no. 4, pp. 594–611, 2000. View at Publisher · View at Google Scholar
  40. M. Sekiguchi, K. Zushida, M. Yoshida, et al., “A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice,” Brain, vol. 132, no. 1, pp. 124–135, 2009. View at Publisher · View at Google Scholar · View at PubMed
  41. D.-A. M. Pillers, R. G. Weleber, D. G. Green, et al., “Effects of dystrophin isoforms on signal transduction through neural retina: genotype-phenotype analysis of Duchenne muscular dystrophy mouse mutants,” Molecular Genetics and Metabolism, vol. 66, no. 2, pp. 100–110, 1999. View at Publisher · View at Google Scholar · View at PubMed
  42. M. F. Costa, A. G. F. Oliveira, C. Feitosa-Santana, M. Zatz, and D. F. Ventura, “Red-green color vision impairment in Duchenne muscular dystrophy,” American Journal of Human Genetics, vol. 80, no. 6, pp. 1064–1075, 2007. View at Publisher · View at Google Scholar · View at PubMed
  43. G. E. Morris, C. Simmons, and N. T. Man, “Apo-dystrophins (DP140 and DP71) and dystrophin splicing isoforms in developing brain,” Biochemical and Biophysical Research Communications, vol. 215, no. 1, pp. 361–367, 1995. View at Publisher · View at Google Scholar
  44. H. G. W. Lidov, S. Selig, and L. M. Kunkel, “Dp140: a novel 140 kDa CNS transcript from the dystrophin locus,” Human Molecular Genetics, vol. 4, no. 3, pp. 329–335, 1995.
  45. T. J. Byers, H. G. W. Lidov, and L. M. Kunkel, “An alternative dystrophin transcript specific to peripheral nerve,” Nature Genetics, vol. 4, no. 1, pp. 77–81, 1993. View at Publisher · View at Google Scholar · View at PubMed
  46. T.-W. Kim, K. Wu, J.-L. Xu, and I. B. Black, “Detection of dystrophin in the postsynaptic density of rat brain and deficiency in a mouse model of Duchenne muscular dystrophy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 23, pp. 11642–11644, 1992. View at Publisher · View at Google Scholar
  47. T. Haenggi, A. Soontornmalai, M. C. Schaub, and J.-M. Fritschy, “The role of utrophin and Dp71 for assembly of different dystrophin-associated protein complexes (DPCs) in the choroid plexus and microvasculature of the brain,” Neuroscience, vol. 129, no. 2, pp. 403–413, 2004. View at Publisher · View at Google Scholar · View at PubMed
  48. D. C. Gorecki and E. A. Barnard, “Specific expression of G-dystrophin (Dp71) in the brain,” NeuroReport, vol. 6, no. 6, pp. 893–896, 1995.
  49. V. Aleman, B. Osorio, O. Chavez, A. Rendon, D. Mornet, and D. Martinez, “Subcellular localization of Dp71 dystrophin isoforms in cultured hippocampal neurons and forebrain astrocytes,” Histochemistry and Cell Biology, vol. 115, no. 3, pp. 243–254, 2001.
  50. D. J. Blake, R. Hawkes, M. A. Benson, and P. W. Beesley, “Different dystrophin-like complexes are expressed in neurons and glia,” Journal of Cell Biology, vol. 147, no. 3, pp. 645–658, 1999. View at Publisher · View at Google Scholar
  51. F. Daoud, A. Candelario-Martinez, J. M. Billard, et al., “Role of mental retardation-associated dystrophin-gene product Dp71 in excitatory synapse organization, synaptic plasticity and behavioral functions,” PloS One, vol. 4, no. 8, p. e6574, 2009.
  52. C. N. Tennyson, H. J. Klamut, and R. G. Worton, “The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced,” Nature Genetics, vol. 9, no. 2, pp. 184–190, 1995.
  53. R. C. Austin, P. L. Howard, V. N. D'Souza, H. J. Klamut, and P. N. Ray, “Cloning and characterization of alternatively spliced isoforms of Dp71,” Human Molecular Genetics, vol. 4, no. 9, pp. 1475–1483, 1995.
  54. H. G. W. Lidov and L. M. Kunkel, “Dp140: alternatively spliced isoforms in brain and kidney,” Genomics, vol. 45, no. 1, pp. 132–139, 1997. View at Publisher · View at Google Scholar · View at PubMed
  55. F. G. Marquez, B. Cisneros, F. Garcia, et al., “Differential expression and subcellular distribution of dystrophin Dp71 isoforms during differentiation process,” Neuroscience, vol. 118, no. 4, pp. 957–966, 2003. View at Publisher · View at Google Scholar
  56. R. C. Austin, G. E. Morris, P. L. Howard, H. J. Klamut, and P. N. Ray, “Expression and synthesis of alternatively spliced variants of Dp71 in adult human brain,” Neuromuscular Disorders, vol. 10, no. 3, pp. 187–193, 2000. View at Publisher · View at Google Scholar
  57. R. C. Austin, J. E. B. Fox, G. H. Werstuck, et al., “Identification of Dp71 isoforms in the platelet membrane cytoskeleton: potential role in thrombin-mediated platelet adhesion,” Journal of Biological Chemistry, vol. 277, no. 49, pp. 47106–47113, 2002. View at Publisher · View at Google Scholar · View at PubMed
  58. M. Ceccarini, G. Rizzo, G. Rosa, C. Chelucci, P. Macioce, and T. C. Petrucci, “A splice variant of Dp71 lacking the syntrophin binding site is expressed in early stages of human neural development,” Developmental Brain Research, vol. 103, no. 1, pp. 77–82, 1997. View at Publisher · View at Google Scholar
  59. H. Jin, S. Tan, J. Hermanowski, et al., “The dystrotelin, dystrophin and dystrobrevin superfamily: new paralogues and old isoforms,” BMC Genomics, vol. 8, article 19, 2007. View at Publisher · View at Google Scholar · View at PubMed
  60. D. R. Love, D. F. Hill, G. Dickson, et al., “An autosomal transcript in skeletal muscle with homology to dystrophin,” Nature, vol. 339, no. 6219, pp. 55–58, 1989.
  61. J. M. Tinsley, D. J. Blake, A. Roche, et al., “Primary structure of dystrophin-related protein,” Nature, vol. 360, no. 6404, pp. 591–593, 1992. View at Publisher · View at Google Scholar · View at PubMed
  62. V. J. Buckle, J. L. Guenet, D. Simon-Chazottes, D. R. Love, and K. E. Davies, “Localisation of a dystrophin-related autosomal gene to 6q24 in man, and to mouse chromosome 10 in the region of the dystrophia muscularis (dy) locus,” Human Genetics, vol. 85, no. 3, pp. 324–326, 1990.
  63. E. Prochniewicz, D. Henderson, J. M. Ervasti, and D. D. Thomas, “Dystrophin and utrophin have distinct effects on the structural dynamics of actin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 19, pp. 7822–7827, 2009. View at Publisher · View at Google Scholar · View at PubMed
  64. S. J. Winder, T. J. Gibson, and J. Kendrick-Jones, “Dystrophin and utrophin: the missing links!,” FEBS Letters, vol. 369, no. 1, pp. 27–33, 1995. View at Publisher · View at Google Scholar
  65. C. L. Dennis, J. M. Tinsley, A. E. Deconinck, and K. E. Davies, “Molecular and functional analysis of the utrophin promoter,” Nucleic Acids Research, vol. 24, no. 9, pp. 1646–1652, 1996. View at Publisher · View at Google Scholar
  66. E. A. Burton, J. M. Tinsley, P. J. Holzfeind, N. R. Rodrigues, and K. E. Davies, “A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 24, pp. 14025–14030, 1999.
  67. T. S. Khurana, S. C. Watkins, P. Chafey, et al., “Immunolocalization and developmental expression of dystrophin related protein in skeletal muscle,” Neuromuscular Disorders, vol. 1, no. 3, pp. 185–194, 1991. View at Publisher · View at Google Scholar
  68. A. P. Weir, E. A. Burton, G. Harrod, and K. E. Davies, “A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle,” Journal of Biological Chemistry, vol. 277, no. 47, pp. 45285–45290, 2002. View at Publisher · View at Google Scholar · View at PubMed
  69. J. M. Tinsley and K. E. Davies, “Utrophin: a potential replacement for dystrophin?” Neuromuscular Disorders, vol. 3, no. 5-6, pp. 537–539, 1993.
  70. K. Ohlendieck, J. M. Ervasti, K. Matsumura, S. D. Kahl, C. J. Leveille, and K. P. Campbell, “Dystrophin-related protein is localized to neuromuscular junctions of adult skeletal muscle,” Neuron, vol. 7, no. 3, pp. 499–508, 1991. View at Publisher · View at Google Scholar
  71. F. Rivier, A. Robert, G. Hugon, and D. Mornet, “Different utrophin and dystrophin properties related to their vascular smooth muscle distributions,” FEBS Letters, vol. 408, no. 1, pp. 94–98, 1997. View at Publisher · View at Google Scholar
  72. J. P. Earnest, G. F. Santos, S. Zuerbig, and J. E. B. Fox, “Dystrophin-related protein in the platelet membrane skeleton. Integrin- induced change in detergent-insolubility and cleavage by calpain in aggregating platelets,” Journal of Biological Chemistry, vol. 270, no. 45, pp. 27259–27265, 1995. View at Publisher · View at Google Scholar
  73. C. N. Lumeng, S. F. Phelps, J. A. Rafael, et al., “Characterization of dystrophin and utrophin diversity in the mouse,” Human Molecular Genetics, vol. 8, no. 4, pp. 593–599, 1999.
  74. K. Matsumura, H. Yamada, T. Shimizu, and K. P. Campbell, “Differential expression of dystrophin, utrophin and dystrophin-associated proteins in peripheral nerve,” FEBS Letters, vol. 334, no. 3, pp. 281–285, 1993. View at Publisher · View at Google Scholar
  75. T. S. Khurana, S. C. Watkins, and L. M. Kunkel, “The subcellular distribution of chromosome 6-encoded dystrophin-related protein in the brain,” Journal of Cell Biology, vol. 119, no. 2, pp. 357–366, 1992. View at Publisher · View at Google Scholar
  76. K. Kamakura, Y. Tadano, M. Kawai, et al., “Dystrophin-related protein is found in the central nervous system of mice at various developmental stages, especially at the postsynaptic membrane,” Journal of Neuroscience Research, vol. 37, no. 6, pp. 728–734, 1994.
  77. P. E. Fort, A. Sene, T. Pannicke, et al., “Kir4.1 and AQP4 associate with Dp71- and utrophin-DAPs complexes in specific and defined microdomains of Muller retinal glial cell membrane,” Glia, vol. 56, no. 6, pp. 597–610, 2008. View at Publisher · View at Google Scholar · View at PubMed
  78. S. M. Baby, S. Bogdanovich, G. Willmann, U. Basu, O. Lozynska, and T. S. Khurana, “Differential expression of utrophin-A and -B promoters in the central nervous system (CNS) of normal and dystrophic mdx mice,” Brain Pathology, vol. 20, no. 2, pp. 323–342, 2010. View at Publisher · View at Google Scholar · View at PubMed
  79. D. J. Blake, J. N. Schofield, R. A. Zuellig, et al., “G-utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 9, pp. 3697–3701, 1995.
  80. J. Wilson, W. Putt, C. Jimenez, and Y. H. Edwards, “Up71 and Up140, two novel transcripts of utrophin that are homologues of short forms of dystrophin,” Human Molecular Genetics, vol. 8, no. 7, pp. 1271–1278, 1999. View at Publisher · View at Google Scholar
  81. E. Fabbrizio, J. Latouche, F. Rivier, G. Hugon, and D. Mornet, “Re-evaluation of the distributions of dystrophin and utrophin in sciatic nerve,” Biochemical Journal, vol. 312, no. 1, pp. 309–314, 1995.
  82. R. A. Zuellig, B. C. Bornhauser, I. Knuesel, F. Heller, J.-M. Fritschy, and M. C. Schaub, “Identification and characterisation of transcript and protein of a new short N-terminal utrophin isoform,” Journal of Cellular Biochemistry, vol. 77, no. 3, pp. 418–431, 2000. View at Publisher · View at Google Scholar
  83. C. Jimenez-Mallebrera, K. Davies, W. Putt, and Y. H. Edwards, “A study of short utrophin isoforms in mice deficient for full-length utrophin,” Mammalian Genome, vol. 14, no. 1, pp. 47–60, 2003. View at Publisher · View at Google Scholar · View at PubMed
  84. R. G. Roberts, T. C. Freeman, E. Kendall, et al., “Characterization of DRP2, a novel human dystrophin homologue,” Nature Genetics, vol. 13, no. 2, pp. 223–226, 1996. View at Publisher · View at Google Scholar · View at PubMed
  85. R. G. Roberts and M. Sheng, “Association of dystrophin-related protein 2 (DRP2) with postsynaptic densities in rat brain,” Molecular and Cellular Neuroscience, vol. 16, no. 5, pp. 674–685, 2000. View at Publisher · View at Google Scholar · View at PubMed
  86. D. L. Sherman, C. Fabrizi, C. Stewart Gillespie, and P. J. Brophy, “Specific disruption of a Schwann cell dystrophin-related protein complex in a demyelinating neuropathy,” Neuron, vol. 30, no. 3, pp. 677–687, 2001. View at Publisher · View at Google Scholar
  87. D. J. Blake, R. Nawrotzki, M. F. Peters, S. C. Froehner, and K. E. Davies, “Isoform diversity of dystrobrevin, the murine 87-kDa postsynaptic protein,” Journal of Biological Chemistry, vol. 271, no. 13, pp. 7802–7810, 1996. View at Publisher · View at Google Scholar
  88. K. Ohlendieck, “Characterisation of the dystrophin-related protein utrophin in highly purified skeletal muscle sarcolemma vesicles,” Biochimica et Biophysica Acta, vol. 1283, no. 2, pp. 215–222, 1996. View at Publisher · View at Google Scholar
  89. D. E. Albrecht and S. C. Froehner, “Syntrophins and dystrobrevins: defining the dystrophin scaffold at synapses,” NeuroSignals, vol. 11, no. 3, pp. 123–129, 2002. View at Publisher · View at Google Scholar
  90. A. Waite, C. L. Tinsley, M. Locke, and D. J. Blake, “The neurobiology of the dystrophin-associated glycoprotein complex,” Annals of Medicine, vol. 41, no. 5, pp. 344–359, 2009. View at Publisher · View at Google Scholar · View at PubMed
  91. R. A. Williamson, M. D. Henry, K. J. Daniels, et al., “Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice,” Human Molecular Genetics, vol. 6, no. 6, pp. 831–841, 1997. View at Publisher · View at Google Scholar
  92. S. A. Moore, F. Saito, J. Chen, et al., “Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy,” Nature, vol. 418, no. 6896, pp. 422–425, 2002. View at Publisher · View at Google Scholar · View at PubMed
  93. F. Muntoni, M. Brockington, S. Torelli, and S. C. Brown, “Defective glycosylation in congenital muscular dystrophies,” Current Opinion in Neurology, vol. 17, no. 2, pp. 205–209, 2004. View at Publisher · View at Google Scholar
  94. D. J. Glass and G. D. Yancopoulos, “Sequential roles of agrin, MuSK and rapsyn during neuromuscular junction formation,” Current Opinion in Neurobiology, vol. 7, no. 3, pp. 379–384, 1997. View at Publisher · View at Google Scholar
  95. M. Cavaldesi, G. Macchia, S. Barca, P. Defilippi, G. Tarone, and T. C. Petrucci, “Association of the dystroglycan complex isolated from bovine brain synaptosomes with proteins involved in signal transduction,” Journal of Neurochemistry, vol. 72, no. 4, pp. 1648–1655, 1999. View at Publisher · View at Google Scholar
  96. M. A. Benson, S. E. Newey, E. Martin-Rendon, R. Hawkes, and D. J. Blake, “Dysbindin, a a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain,” Journal of Biological Chemistry, vol. 276, no. 26, pp. 24232–24241, 2001. View at Publisher · View at Google Scholar · View at PubMed
  97. K. Talbot, D.-S. Cho, W.-Y. Ong, et al., “Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin,” Human Molecular Genetics, vol. 15, no. 20, pp. 3041–3054, 2006. View at Publisher · View at Google Scholar · View at PubMed
  98. S. Taneichi-Kuroda, S. Taya, T. Hikita, Y. Fujino, and K. Kaibuchi, “Direct interaction of Dysbindin with the AP-3 complex via its μ subunit,” Neurochemistry International, vol. 54, no. 7, pp. 431–438, 2009. View at Publisher · View at Google Scholar · View at PubMed
  99. A. E. Deconinck, A. C. Potter, J. M. Tinsley, et al., “Postsynaptic abnormalities at the neuromuscular junctions of utrophin-deficient mice,” Journal of Cell Biology, vol. 136, no. 4, pp. 883–894, 1997. View at Publisher · View at Google Scholar
  100. R. M. Grady, J. P. Merlie, and J. R. Sanes, “Subtle neuromuscular defects in utrophin-deficient mice,” Journal of Cell Biology, vol. 136, no. 4, pp. 871–882, 1997. View at Publisher · View at Google Scholar
  101. M. E. Adams, N. Kramarcy, S. P. Krall, et al., “Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin,” Journal of Cell Biology, vol. 150, no. 6, pp. 1385–1398, 2000. View at Publisher · View at Google Scholar
  102. G. B. Banks, C. Fuhrer, M. E. Adams, and S. C. Froehner, “The postsynaptic submembrane machinery at the neuromuscular junction: requirement for rapsyn and the utrophin/dystrophin-associated complex,” Brain Cell Biology, vol. 32, no. 5–8, pp. 709–726, 2003.
  103. C. Jacobson, P. D. Cote, S. G. Rossi, R. L. Rotundo, and S. Carbonetto, “The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane,” Journal of Cell Biology, vol. 153, no. 3, pp. 435–450, 2001.
  104. M. Akaaboune, R. M. Grady, S. Turney, J. R. Sanes, and J. W. Lichtman, “Neurotransmitter receptor dynamics studied in vivo by reversible photo-unbinding of fluorescent ligands,” Neuron, vol. 34, no. 6, pp. 865–876, 2002. View at Publisher · View at Google Scholar
  105. A. K. Peter, J. L. Marshall, and R. H. Crosbie, “Sarcospan reduces dystrophic pathology: stabilization of the utrophin-glycoprotein complex,” Journal of Cell Biology, vol. 183, no. 3, pp. 419–427, 2008. View at Publisher · View at Google Scholar · View at PubMed
  106. M. F. Peters, M. E. Adams, and S. C. Froehner, “Differential association of syntrophin pairs with the dystrophin complex,” Journal of Cell Biology, vol. 138, no. 1, pp. 81–93, 1997. View at Publisher · View at Google Scholar
  107. N. R. Kramarcy and R. Sealock, “Syntrophin isoforms at the neuromuscular junction: developmental time course and differential localization,” Molecular and Cellular Neurosciences, vol. 15, no. 3, pp. 262–274, 2000. View at Publisher · View at Google Scholar · View at PubMed
  108. C. Pastoret and A. Sebille, “mdx mice show progressive weakness and muscle deterioration with age,” Journal of the Neurological Sciences, vol. 129, no. 2, pp. 97–105, 1995. View at Publisher · View at Google Scholar
  109. R. M. Grady, D. F. Wozniak, K. K. Ohlemiller, and J. R. Sanes, “Cerebellar synaptic defects and abnormal motor behavior in mice lacking α- and β-dystrobrevin,” Journal of Neuroscience, vol. 26, no. 11, pp. 2841–2851, 2006. View at Publisher · View at Google Scholar · View at PubMed
  110. C. Vaillend, J.-M. Billard, and S. Laroche, “Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmdmdx mouse,” Neurobiology of Disease, vol. 17, no. 1, pp. 10–20, 2004. View at Publisher · View at Google Scholar · View at PubMed
  111. A. K. Sesay, M. L. Errington, L. Levita, and T. V. P. Bliss, “Spatial learning and hippocampal long-term potentiation are not impaired in mdx mice,” Neuroscience Letters, vol. 211, no. 3, pp. 207–210, 1996. View at Publisher · View at Google Scholar
  112. C. Vaillend, J.-M. Billard, T. Claudepierre, A. Rendon, P. Dutar, and A. Ungerer, “Spatial discrimination learning and CA1 hippocampal synaptic plasticity in mdx and mdx(3cv) mice lacking dystrophin gene products,” Neuroscience, vol. 86, no. 1, pp. 53–66, 1998. View at Publisher · View at Google Scholar
  113. F. Muntoni, A. Mateddu, and G. Serra, “Passive avoidance behaviour deficit in the mdx mouse,” Neuromuscular Disorders, vol. 1, no. 2, pp. 121–123, 1991. View at Publisher · View at Google Scholar
  114. C. Vaillend, A. Rendon, R. Misslin, and A. Ungerer, “Influence of dystrophin-gene mutation on mdx mouse behavior. I. Retention deficits at long delays in spontaneous alternation and bar-pressing tasks,” Behavior Genetics, vol. 25, no. 6, pp. 569–579, 1995. View at Publisher · View at Google Scholar
  115. C. Vaillend, A. Ungerer, and J.-M. Billard, “Facilitated NMDA receptor-mediated synaptic plasticity in the hippocampal CA1 area of dystrophin-deficient mice,” Synapse, vol. 33, no. 1, pp. 59–70, 1999. View at Publisher · View at Google Scholar
  116. C. Vaillend and A. Ungerer, “Behavioral characterization of mdx3cv mice deficient in C-terminal dystrophins,” Neuromuscular Disorders, vol. 9, no. 5, pp. 296–304, 1999. View at Publisher · View at Google Scholar
  117. M. F. Mehler, K. Z. Haas, J. A. Kessler, and P. K. Stanton, “Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 6, pp. 2461–2465, 1992.
  118. D. Carretta, M. Santarelli, D. Vanni, et al., “Cortical and brainstem neurons containing calcium-binding proteins in a murine model of Duchenne's muscular dystrophy: selective changes in the sensorimotor cortex,” Journal of Comparative Neurology, vol. 456, no. 1, pp. 48–59, 2003. View at Publisher · View at Google Scholar · View at PubMed
  119. R. Miranda, C. Sebrie, J. Degrouard, et al., “Reorganization of inhibitory synapses and increased PSD length of perforated excitatory synapses in hippocampal area CA1 of dystrophin-deficient mdx mice,” Cerebral Cortex, vol. 19, no. 4, pp. 876–888, 2009. View at Publisher · View at Google Scholar · View at PubMed
  120. J. L. Anderson, S. I. Head, and J. W. Morley, “Long-term depression is reduced in cerebellar Purkinje cells of dystrophin-deficient mdx mice,” Brain Research, vol. 1019, no. 1-2, pp. 289–292, 2004. View at Publisher · View at Google Scholar · View at PubMed
  121. J. L. Anderson, J. W. Morley, and S. I. Head, “Enhanced homosynaptic LTD in cerebellar Purkinje cells of the dystrophic mdx mouse,” Muscle and Nerve, vol. 41, no. 3, pp. 329–334, 2010. View at Publisher · View at Google Scholar · View at PubMed
  122. J. E. Anderson, “A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells,” Molecular Biology of the Cell, vol. 11, no. 5, pp. 1859–1874, 2000.
  123. M. G. D'Angelo and N. Bresolin, “Cognitive impairment in neuromuscular disorders,” Muscle and Nerve, vol. 34, no. 1, pp. 16–33, 2006. View at Publisher · View at Google Scholar · View at PubMed
  124. I. Brunig, A. Suter, I. Knuesel, B. Luscher, and J.-M. Fritschy, “GABAergic terminals are required for postsynaptic clustering of dystrophin but not of GABAA receptors and gephyrin,” Journal of Neuroscience, vol. 22, no. 12, pp. 4805–4813, 2002.
  125. S. Levi, R. M. Grady, M. D. Henry, K. P. Campbell, J. R. Sanes, and A. M. Craig, “Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation,” Journal of Neuroscience, vol. 22, no. 11, pp. 4274–4285, 2002.
  126. I. Knuesel, M. Mastrocola, R. A. Zuellig, B. Bornhauser, M. C. Schaub, and J.-M. Fritschy, “Altered synaptic clustering of GABAA receptors in mice lacking dystrophin (mdx mice),” European Journal of Neuroscience, vol. 11, no. 12, pp. 4457–4462, 1999.
  127. J.-M. Fritschy, C. Schweizer, I. Brunig, and B. Luscher, “Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors),” Biochemical Society Transactions, vol. 31, no. 4, pp. 889–892, 2003. View at Publisher · View at Google Scholar
  128. A. M. Craig and Y. Kang, “Neurexin-neuroligin signaling in synapse development,” Current Opinion in Neurobiology, vol. 17, no. 1, pp. 43–52, 2007. View at Publisher · View at Google Scholar · View at PubMed
  129. I. Knuesel, R. A. Zuellig, M. C. Schaub, and J.-M. Fritschy, “Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy,” European Journal of Neuroscience, vol. 13, no. 6, pp. 1113–1124, 2001. View at Publisher · View at Google Scholar
  130. J. L. Anderson, S. I. Head, and J. W. Morley, “Altered inhibitory input to Purkinje cells of dystrophin-deficient mice,” Brain Research, vol. 982, no. 2, pp. 280–283, 2003. View at Publisher · View at Google Scholar
  131. C. Vaillend and J.-M. Billard, “Facilitated CA1 hippocampal synaptic plasticity in dystrophin-deficient mice: role of GABAA receptors?” Hippocampus, vol. 12, no. 6, pp. 713–717, 2002. View at Publisher · View at Google Scholar · View at PubMed
  132. S. L. L. Kueh, S. I. Head, and J. W. Morley, “GABAA receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice,” Clinical and Experimental Pharmacology and Physiology, vol. 35, no. 2, pp. 207–210, 2008. View at Publisher · View at Google Scholar · View at PubMed
  133. L. Graciotti, A. Minelli, D. Minciacchi, A. Procopio, and G. Fulgenzi, “GABAergic miniature spontaneous activity is increased in the CA1 hippocampal region of dystrophic mdx mice,” Neuromuscular Disorders, vol. 18, no. 3, pp. 220–226, 2008. View at Publisher · View at Google Scholar · View at PubMed
  134. C. Del Tongo, D. Carretta, G. Fulgenzi, C. Catini, and D. Minciacchi, “Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse,” Acta Neuropathologica, vol. 118, no. 6, pp. 803–812, 2009. View at Publisher · View at Google Scholar · View at PubMed
  135. Y. Yoshihara, H. Onodera, K. Iinuma, and Y. Itoyama, “Abnormal kainic acid receptor density and reduced seizure susceptibility in dystrophin-deficient mdx mice,” Neuroscience, vol. 117, no. 2, pp. 391–395, 2003. View at Publisher · View at Google Scholar
  136. G. De Sarro, G. F. Ibbadu, R. Marra, et al., “Seizure susceptibility to various convulsant stimuli in dystrophin-deficient mdx mice,” Neuroscience Research, vol. 50, no. 1, pp. 37–44, 2004. View at Publisher · View at Google Scholar · View at PubMed
  137. R. Coccurello, C. Castellano, P. Paggi, A. Mele, and A. Oliverio, “Genetically dystrophic mdx/mdx mice exhibit decreased response to nicotine in passive avoidance,” NeuroReport, vol. 13, no. 9, pp. 1219–1222, 2002.
  138. A. Del Signore, C. Gotti, M. E. De Stefano, M. Moretti, and P. Paggi, “Dystrophin stabilizes α3- but not α7-containing nicotinic acetylcholine receptor subtypes at the postsynaptic apparatus in the mouse superior cervical ganglion,” Neurobiology of Disease, vol. 10, no. 1, pp. 54–66, 2002. View at Publisher · View at Google Scholar
  139. B. Nico, A. Frigeri, G. P. Nicchia, et al., “Severe alterations of endothelial and glial cells in the blood-brain barrier of dystrophic mdx mice,” Glia, vol. 42, no. 3, pp. 235–251, 2003. View at Publisher · View at Google Scholar · View at PubMed
  140. B. Nico, G. P. Nicchia, A. Frigeri, et al., “Altered blood-brain barrier development in dystrophic MDX mice,” Neuroscience, vol. 125, no. 4, pp. 921–935, 2004. View at Publisher · View at Google Scholar · View at PubMed
  141. B. Nico, P. Corsi, R. Ria, et al., “Increased matrix-metalloproteinase-2 and matrix-metalloproteinase-9 expression in the brain of dystrophic mdx mouse,” Neuroscience, vol. 140, no. 3, pp. 835–848, 2006. View at Publisher · View at Google Scholar · View at PubMed
  142. B. Nico, D. Mangieri, E. Crivellato, et al., “HIF activation and VEGF overexpression are coupled with ZO-1 up-phosphorylation in the brain of dystrophic MDX mouse,” Brain Pathology, vol. 17, no. 4, pp. 399–406, 2007. View at Publisher · View at Google Scholar · View at PubMed
  143. A. Baydur, I. Gilgoff, W. Prentice, M. Carlson, and D. A. Fischer, “Decline in respiratory function and experience with long-term assisted ventilation in advanced Duchenne's muscular dystrophy,” Chest, vol. 97, no. 4, pp. 884–889, 1990.
  144. R. Sarig, V. Mezger-Lallemand, I. Gitelman, et al., “Targeted inactivation of Dp71, the major non-muscle product of the DMD gene: differential activity of the Dp71 promoter during development,” Human Molecular Genetics, vol. 8, no. 1, pp. 1–10, 1999. View at Publisher · View at Google Scholar
  145. C. Vaillend, R. Poirier, and S. Laroche, “Genes, plasticity and mental retardation,” Behavioural Brain Research, vol. 192, no. 1, pp. 88–105, 2008. View at Publisher · View at Google Scholar · View at PubMed
  146. M. Amiry-Moghaddam, R. Xue, F. M. Haug, et al., “Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia,” FASEB Journal, vol. 18, no. 3, pp. 542–544, 2004.
  147. Z. Vajda, M. Pedersen, E.-M. Fuchtbauer, et al., “Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 20, pp. 13131–13136, 2002. View at Publisher · View at Google Scholar · View at PubMed
  148. G. P. Nicchia, A. Rossi, U. Nudel, M. Svelto, and A. Frigeri, “Dystrophin-dependent and -independent AQP4 pools are expressed in the mouse brain,” Glia, vol. 56, no. 8, pp. 869–876, 2008. View at Publisher · View at Google Scholar · View at PubMed
  149. H. Hibino, A. Fujita, K. Iwai, M. Yamada, and Y. Kurachi, “Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes,” Journal of Biological Chemistry, vol. 279, no. 42, pp. 44065–44073, 2004. View at Publisher · View at Google Scholar · View at PubMed
  150. N. C. Connors, M. E. Adams, S. C. Froehner, and P. Kofuji, “The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via α-syntrophin in glia,” Journal of Biological Chemistry, vol. 279, no. 27, pp. 28387–28392, 2004. View at Publisher · View at Google Scholar · View at PubMed
  151. E. Guadagno and H. Moukhles, “Laminin-induced aggregation of the inwardly rectifying potassium channel, Kir4.1, and the water-permeable channel, AQP4, via a dystroglycan-containing complex in astrocytes,” Glia, vol. 47, no. 2, pp. 138–149, 2004. View at Publisher · View at Google Scholar · View at PubMed
  152. A. Sene, R. Tadayoni, T. Pannicke, et al., “Functional implication of Dp71 in osmoregulation and vascular permeability of the retina,” PloS One, vol. 4, no. 10, article e7329, 2009. View at Publisher · View at Google Scholar · View at PubMed
  153. C. Dalloz, R. Sarig, P. Fort, et al., “Targeted inactivation of dystrophin gene product Dp71: phenotypic impact in mouse retina,” Human Molecular Genetics, vol. 12, no. 13, pp. 1543–1554, 2003. View at Publisher · View at Google Scholar
  154. R. Benabdesselam, A. Sene, D. Raison, et al., “A deficit of brain dystrophin 71 impairs hypothalamic osmostat,” Journal of Neuroscience Research, vol. 88, no. 2, pp. 324–334, 2010. View at Publisher · View at Google Scholar · View at PubMed
  155. S. Saadoun, M. J. Tait, A. Reza, et al., “AQP4 gene deletion in mice does not alter blood-brain barrier integrity or brain morphology,” Neuroscience, vol. 161, no. 3, pp. 764–772, 2009. View at Publisher · View at Google Scholar · View at PubMed
  156. D. C. Gorecki, K. Lukasiuk, A. Szklarczyk, and L. Kaczmarek, “Kainate-evoked changes in dystrophin messenger RNA levels in the rat hippocampus,” Neuroscience, vol. 84, no. 2, pp. 467–477, 1998. View at Publisher · View at Google Scholar
  157. M. Ceccarini, P. Macioce, B. Panetta, and T. C. Petrucci, “Expression of dystrophin-associated proteins during neuronal differentiation of P19 embryonal carcinoma cells,” Neuromuscular Disorders, vol. 12, no. 1, pp. 36–48, 2002. View at Publisher · View at Google Scholar
  158. J. Cerna, D. Cerecedo, A. Ortega, et al., “Dystrophin Dp71f associates with the β1-integrin adhesion complex to modulate PC12 cell adhesion,” Journal of Molecular Biology, vol. 362, no. 5, pp. 954–965, 2006. View at Publisher · View at Google Scholar · View at PubMed
  159. A. E. Deconinck, J. A. Rafael, J. A. Skinner, et al., “Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy,” Cell, vol. 90, no. 4, pp. 717–727, 1997. View at Publisher · View at Google Scholar
  160. R. M. Grady, H. Teng, M. C. Nichol, J. C. Cunningham, R. S. Wilkinson, and J. R. Sanest, “Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy,” Cell, vol. 90, no. 4, pp. 729–738, 1997. View at Publisher · View at Google Scholar
  161. I. Knuesel, V. Riban, R. A. Zuellig, et al., “Increased vulnerability to kainate-induced seizures in utrophin-knockout mice,” European Journal of Neuroscience, vol. 15, no. 9, pp. 1474–1484, 2002. View at Publisher · View at Google Scholar
  162. K. Culligan, L. Glover, P. Dowling, and K. Ohlendieck, “Brain dystrophin-glycoprotein complex: persistent expression of beta-dystroglycan, impaired oligomerization of Dp71 and up-regulation of utrophins in animal models of muscular dystrophy,” BMC Cell Biology, vol. 2, article 2, 2001.
  163. K. Hnia, S. Tuffery-Giraud, M. Vermaelen, et al., “Pathological pattern of Mdx mice diaphragm correlates with gradual expression of the short utrophin isoform Up71,” Biochimica et Biophysica Acta, vol. 1762, no. 3, pp. 362–372, 2006. View at Publisher · View at Google Scholar · View at PubMed
  164. S. Bogdanovich, K. J. Perkins, T. O. B. Krag, and T. S. Khurana, “Therapeutics for Duchenne muscular dystrophy: current approaches and future directions,” Journal of Molecular Medicine, vol. 82, no. 2, pp. 102–115, 2004. View at Publisher · View at Google Scholar · View at PubMed
  165. C. Angelini, E. Pegoraro, E. Turella, M. T. Intino, A. Pini, and C. Costa, “Deflazacort in Duchenne dystrophy: study of long-term effect,” Muscle and Nerve, vol. 17, no. 4, pp. 386–391, 1994.
  166. M. D. Bonifati, G. Ruzza, P. Bonometto, et al., “A multicenter, double-blind, randomized trial of deflazacort versus prednisone in duchenne muscular dystrophy,” Muscle and Nerve, vol. 23, no. 9, pp. 1344–1347, 2000. View at Publisher · View at Google Scholar
  167. T. A. Partridge, J. E. Morgan, G. R. Coulton, E. P. Hoffman, and L. M. Kunkel, “Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts,” Nature, vol. 337, no. 6203, pp. 176–179, 1989.
  168. B. Péault, M. Rudnicki, Y. Torrente, et al., “Stem and progenitor cells in skeletal muscle development, maintenance, and therapy,” Molecular Therapy, vol. 15, no. 5, pp. 867–877, 2007. View at Publisher · View at Google Scholar · View at PubMed
  169. E. Gussoni, R. R. Bennett, K. R. Muskiewicz, et al., “Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation,” Journal of Clinical Investigation, vol. 110, no. 6, pp. 807–814, 2002. View at Publisher · View at Google Scholar
  170. S. Ebihara, G.-H. Guibinga, R. Gilbert, et al., “Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice,” Physiological Genomics, vol. 3, no. 3, pp. 133–144, 2000.
  171. G. M. Smythe, S. I. Hodgetts, and M. D. Grounds, “Problems and solutions in myoblast transfer therapy,” Journal of Cellular and Molecular Medicine, vol. 5, no. 1, pp. 33–47, 2001.
  172. D. Cerecedo, R. Mondragon, A. Candelario, et al., “Utrophins compensate for Dp71 absence in mdx3cv in adhered platelets,” Blood Coagulation and Fibrinolysis, vol. 19, no. 1, pp. 39–47, 2008. View at Publisher · View at Google Scholar · View at PubMed
  173. K. P. Campbell and R. H. Crosbie, “Utrophin to the rescue,” Nature, vol. 384, no. 6607, pp. 308–309, 1996. View at Publisher · View at Google Scholar · View at PubMed
  174. J. M. Tinsley, A. C. Potter, S. R. Phelps, R. Fisher, J. I. Trickett, and K. E. Davies, “Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene,” Nature, vol. 384, no. 6607, pp. 349–353, 1996. View at Publisher · View at Google Scholar · View at PubMed
  175. G. L. Odom, P. Gregorevic, J. M. Allen, E. Finn, and J. S. Chamberlain, “Microutrophin delivery through rAAV6 increases lifespan and improves muscle function in dystrophic dystrophin/Utrophin-deficient mice,” Molecular Therapy, vol. 16, no. 9, pp. 1539–1545, 2008. View at Publisher · View at Google Scholar · View at PubMed
  176. E. Chaubourt, P. Fossier, G. Baux, C. Leprince, M. Israel, and S. De La Porte, “Nitric oxide and L-arginine cause an accumulation of utrophin at the sarcolemma: a possible compensation for dystrophin loss in Duchenne muscular dystrophy,” Neurobiology of Disease, vol. 6, no. 6, pp. 499–507, 1999. View at Publisher · View at Google Scholar · View at PubMed
  177. E. R. Barton, L. Morris, M. Kawana, L. T. Bish, and T. Toursel, “Systemic administration of L-arginine benefits mdx skeletal muscle function,” Muscle and Nerve, vol. 32, no. 6, pp. 751–760, 2005. View at Publisher · View at Google Scholar · View at PubMed
  178. V. Voisin, C. Sebrie, S. Matecki, et al., “L-arginine improves dystrophic phenotype in mdx mice,” Neurobiology of Disease, vol. 20, no. 1, pp. 123–130, 2005. View at Publisher · View at Google Scholar · View at PubMed
  179. F. Benabdellah, A. Seyer, L. Quinton, D. Touboul, A. Brunelle, and O. Laprévote, “Mass spectrometry imaging of rat brain sections: nanomolar sensitivity with MALDI versus nanometer resolution by TOF-SIMS,” Analytical and Bioanalytical Chemistry, vol. 396, no. 1, pp. 151–162, 2010. View at Publisher · View at Google Scholar · View at PubMed
  180. K. Hnia, J. Gayraud, G. Hugon, et al., “L-arginine decreases inflammation and modulates the nuclear factor-κB/matrix metalloproteinase cascade in Mdx muscle fibers,” American Journal of Pathology, vol. 172, no. 6, pp. 1509–1519, 2008. View at Publisher · View at Google Scholar · View at PubMed
  181. D. Chazalette, K. Hnia, F. Rivier, G. Hugon, and D. Mornet, “α7B integrin changes in mdx mouse muscles after L-arginine administration,” FEBS Letters, vol. 579, no. 5, pp. 1079–1084, 2005. View at Publisher · View at Google Scholar · View at PubMed
  182. B. Deng, D. Glanzman, and J. G. Tidball, “Nitric oxide generated by muscle corrects defects in hippocampal neurogenesis and neural differentiation caused by muscular dystrophy,” Journal of Physiology, vol. 587, no. 8, pp. 1769–1778, 2009. View at Publisher · View at Google Scholar · View at PubMed
  183. T. S. Khurana, A. G. Rosmarin, J. Shang, T. O. B. Krag, S. Das, and S. Gammeltoft, “Activation of utrophin promoter by heregulin via the ets-related transcription factor complex GA-binding protein α/β,” Molecular Biology of the Cell, vol. 10, no. 6, pp. 2075–2086, 1999.
  184. T. O. B. Krag, S. Bogdanovich, C. J. Jensen, et al., “Heregulin ameliorates the dystrophic phenotype in mdx mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 38, pp. 13856–13860, 2004. View at Publisher · View at Google Scholar · View at PubMed
  185. A. J. Kastin, V. Akerstrom, and W. Pan, “Neuregulin-1-β1 enters brain and spinal cord by receptor-mediated transport,” Journal of Neurochemistry, vol. 88, no. 4, pp. 965–970, 2004.
  186. J. V. Chakkalakal, M.-A. Harrison, S. Carbonetto, E. Chin, R. N. Michel, and B. J. Jasmin, “Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice,” Human Molecular Genetics, vol. 13, no. 4, pp. 379–388, 2004. View at Publisher · View at Google Scholar · View at PubMed
  187. P. Miura and B. J. Jasmin, “Utrophin upregulation for treating Duchenne or Becker muscular dystrophy: how close are we?” Trends in Molecular Medicine, vol. 12, no. 3, pp. 122–129, 2006. View at Publisher · View at Google Scholar · View at PubMed
  188. S. J. G. St-Pierre, J. V. Chakkalakal, S. M. Kolodziejczyk, J. C. Knudson, B. J. Jasmin, and L. A. Megeney, “Glucocorticoid treatment alleviates dystrophic myofiber pathology by activation of the calcineurin/NF-AT pathway,” FASEB Journal, vol. 18, no. 15, pp. 1937–1939, 2004. View at Publisher · View at Google Scholar · View at PubMed
  189. A. O. Gramolini and B. J. Jasmin, “Expression of the utrophin gene during myogenic differentiation,” Nucleic Acids Research, vol. 27, no. 17, pp. 3603–3609, 1999. View at Publisher · View at Google Scholar
  190. P. Miura, J. V. Chakkalakal, L. Boudreault, et al., “Pharmacological activation of PPARβ/δ stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice,” Human Molecular Genetics, vol. 18, no. 23, pp. 4640–4649, 2009. View at Publisher · View at Google Scholar · View at PubMed
  191. S. F. Nelson, R. H. Crosbie, M. C. Miceli, and M. J. Spencer, “Emerging genetic therapies to treat Duchenne muscular dystrophy,” Current Opinion in Neurology, vol. 22, no. 5, pp. 532–538, 2009. View at Publisher · View at Google Scholar · View at PubMed
  192. P. Dunant, M. C. Walter, G. Karpati, and H. Lochmuller, “Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle,” Muscle and Nerve, vol. 27, no. 5, pp. 624–627, 2003. View at Publisher · View at Google Scholar · View at PubMed
  193. A. De Luca, B. Nico, J.-F. Rolland, et al., “Gentamicin treatment in exercised mdx mice: identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle,” Neurobiology of Disease, vol. 32, no. 2, pp. 243–253, 2008. View at Publisher · View at Google Scholar · View at PubMed
  194. K. R. Wagner, S. Hamed, D. W. Hadley, et al., “Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations,” Annals of Neurology, vol. 49, no. 6, pp. 706–711, 2001. View at Publisher · View at Google Scholar
  195. L. Du, R. Damoiseaux, S. Nahas, et al., “Nonaminoglycoside compounds induce readthrough of nonsense mutations,” Journal of Experimental Medicine, vol. 206, no. 10, pp. 2285–2297, 2009. View at Publisher · View at Google Scholar · View at PubMed
  196. E. M. Welch, E. R. Barton, J. Zhuo, et al., “PTC124 targets genetic disorders caused by nonsense mutations,” Nature, vol. 447, no. 7140, pp. 87–91, 2007. View at Publisher · View at Google Scholar · View at PubMed
  197. S. Hirawat, E. M. Welch, G. L. Elfring, et al., “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers,” Journal of Clinical Pharmacology, vol. 47, no. 4, pp. 430–444, 2007. View at Publisher · View at Google Scholar · View at PubMed
  198. A. Aartsma-Rus, I. Fokkema, J. Verschuuren, et al., “Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations,” Human Mutation, vol. 30, no. 3, pp. 293–299, 2009. View at Publisher · View at Google Scholar · View at PubMed
  199. J. C. van Deutekom, A. A. Janson, I. B. Ginjaar, et al., “Local dystrophin restoration with antisense oligonucleotide PRO051,” The New England Journal of Medicine, vol. 357, no. 26, pp. 2677–2686, 2007. View at Publisher · View at Google Scholar · View at PubMed
  200. M. Kinali, V. Arechavala-Gomeza, L. Feng, et al., “Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study,” The Lancet Neurology, vol. 8, no. 10, pp. 918–928, 2009. View at Publisher · View at Google Scholar
  201. H. M. Moulton, B. Wu, N. Jearawiriyapaisarn, P. Sazani, Q. L. Lu, and R. Kole, “Peptide-morpholino conjugate: a promising therapeutic for duchenne muscular dystrophy,” Annals of the New York Academy of Sciences, vol. 1175, pp. 55–60, 2009. View at Publisher · View at Google Scholar · View at PubMed
  202. A. Goyenvalle, A. Vulin, F. Fougerousse, et al., “Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping,” Science, vol. 306, no. 5702, pp. 1796–1799, 2004. View at Publisher · View at Google Scholar · View at PubMed
  203. A. Goyenvalle, A. Babbs, G.-J. B. van Ommen, L. Garcia, and K. E. Davies, “Enhanced exon-skipping induced by U7 snRNA carrying a splicing silencer sequence: promising tool for DMD therapy,” Molecular Therapy, vol. 17, no. 7, pp. 1234–1240, 2009. View at Publisher · View at Google Scholar · View at PubMed
  204. C. Wang, C.-M. Wang, K. R. Clark, and T. J. Sferra, “Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain,” Gene Therapy, vol. 10, no. 17, pp. 1528–1534, 2003. View at Publisher · View at Google Scholar · View at PubMed
  205. C. Burger, O. S. Gorbatyuk, M. J. Velardo, et al., “Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system,” Molecular Therapy, vol. 10, no. 2, pp. 302–317, 2004. View at Publisher · View at Google Scholar · View at PubMed