Molecular, Physiological, and Motor Performance Defects in DMSXL Mice Carrying >1,000 CTG Repeats from the Human DM1 Locus

English version České info

Myotonic dystrophy type 1 (DM1) is caused by an unstable CTG repeat expansion in the 3′UTR of the DM protein kinase (DMPK) gene. DMPK transcripts carrying CUG expansions form nuclear foci and affect splicing regulation of various RNA transcripts. Furthermore, bidirectional transcription over the DMPK gene and non-conventional RNA translation of repeated transcripts have been described in DM1. It is clear now that this disease may involve multiple pathogenic pathways including changes in gene expression, RNA stability and splicing regulation, protein translation, and micro–RNA metabolism. We previously generated transgenic mice with 45-kb of the DM1 locus and >300 CTG repeats (DM300 mice). After successive breeding and a high level of CTG repeat instability, we obtained transgenic mice carrying >1,000 CTG (DMSXL mice). Here we described for the first time the expression pattern of the DMPK sense transcripts in DMSXL and human tissues. Interestingly, we also demonstrate that DMPK antisense transcripts are expressed in various DMSXL and human tissues, and that both sense and antisense transcripts accumulate in independent nuclear foci that do not co-localize together. Molecular features of DM1-associated RNA toxicity in DMSXL mice (such as foci accumulation and mild missplicing), were associated with high mortality, growth retardation, and muscle defects (abnormal histopathology, reduced muscle strength, and lower motor performances). We have found that lower levels of IGFBP-3 may contribute to DMSXL growth retardation, while increased proteasome activity may affect muscle function. These data demonstrate that the human DM1 locus carrying very large expansions induced a variety of molecular and physiological defects in transgenic mice, reflecting DM1 to a certain extent. As a result, DMSXL mice provide an animal tool to decipher various aspects of the disease mechanisms. In addition, these mice can be used to test the preclinical impact of systemic therapeutic strategies on molecular and physiological phenotypes.

Vyšlo v časopise: Molecular, Physiological, and Motor Performance Defects in DMSXL Mice Carrying >1,000 CTG Repeats from the Human DM1 Locus. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003043
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003043

Souhrn

Zdroje

1. Harper PS (2001) Myotonic Dystrophy, 3rd edition; Saunders WB, editor. London Philadelphia.

2. EchenneB, RideauA, RoubertieA, SebireG, RivierF, et al. (2008) Myotonic dystrophy type I in childhood Long-term evolution in patients surviving the neonatal period. Eur J Paediatr Neurol 12: 210–223.

3. AslanidisC, JansenG, AmemiyaC, ShutlerG, MahadevanM, et al. (1992) Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature 355: 548–551.

4. BrookJD, McCurrachME, HarleyHG, BucklerHJ, ChurchD, et al. (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68: 799–808.

5. FuYH, PizzutiA, FenwickRGJr, KingJ, RajnarayanS, et al. (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255: 1256–1258.

6. Gomes-PereiraM, CooperTA, GourdonG (2011) Myotonic dystrophy mouse models: towards rational therapy development. Trends Mol Med 17: 506–517.

7. SicotG, GourdonG, Gomes-PereiraM (2011) Myotonic dystrophy, when simple repeats reveal complex pathogenic entities: new findings and future challenges. Hum Mol Genet 20: R116–123.

8. TimchenkoLT (1999) Myotonic Dystrophy: the role of RNA CUG triplet repeats. Am J Hum Genet 64: 360–364.

9. MillerJW, UrbinatiCR, Teng-UmnuayP, StenbergMG, ByrneBJ, et al. (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19: 4439–4448.

10. MankodiA, UrbinatiCR, YuanQP, MoxleyRT, SansoneV, et al. (2001) Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet 10: 2165–2170.

11. FardaeiM, LarkinK, BrookJD, HamshereMG (2001) In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res 29: 2766–2771.

12. CharletBN, SavkurRS, SinghG, PhilipsAV, GriceEA, et al. (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10: 45–53.

13. FardaeiM, RogersMT, ThorpeHM, LarkinK, HamshereMG, et al. (2002) Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet 11: 805–814.

14. FaustinoNA, CooperTA (2003) Pre-mRNA splicing and human disease. Genes Dev 17: 419–437.

15. RanumLP, DayJW (2002) Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2. Curr Neurol Neurosci Rep 2: 465–470.

16. ChoDH, ThienesCP, MahoneySE, AnalauE, FilippovaGN, et al. (2005) Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell 20: 483–489.

17. ZuT, GibbensB, DotyNS, Gomes-PereiraM, HuguetA, et al. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108: 260–265.

18. SeznecH, Lia-BaldiniAS, DurosC, FouquetC, LacroixC, et al. (2000) Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. Hum Mol Genet 9: 1185–1194.

19. GourdonG, RadvanyiF, LiaAS, DurosC, BlancheM, et al. (1997) Moderate instability of a 55 CTG repeat in transgenic mice carrying a 45 kb genomic region from an affected DM patient. Nat Genet 15: 190–192.

20. LiaAS, SeznecH, Hofmann-RadvanyiH, RadvanyiF, DurosC, et al. (1998) Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities. Hum Mol Genet 7: 1285–1291.

21. PanaitePA, GanteletE, KraftsikR, GourdonG, KuntzerT, et al. (2008) Myotonic dystrophy transgenic mice exhibit pathologic abnormalities in diaphragm neuromuscular junctions and phrenic nerves. J Neuropathol Exp Neurol 67: 763–772.

22. VignaudA, FerryA, HuguetA, BaraibarM, TrolletC, et al. (2010) Progressive skeletal muscle weakness in transgenic mice expressing CTG expansions is associated with the activation of the ubiquitin-proteasome pathway. Neuromuscul Disord 20: 319–325.

23. Gomes-PereiraM, FoiryL, NicoleA, HuguetA, JunienC, et al. (2007) CTG trinucleotide repeat “big jumps”: large expansions, small mice. PLoS Genet 3: e52 doi:10.1371/journal.pgen.0030052.

24. SeznecH, AgbulutO, SergeantN, SavouretC, GhestemA, et al. (2001) Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet 10: 2717–2726.

25. Guiraud-DoganC, HuguetA, Gomes-PereiraM, BrissonE, BassezG, et al. (2007) DM1 CTG expansions affect insulin receptor isoforms expression in various tissues of transgenic mice. Biochim Biophys Acta 1772: 1183–1191.

26. WojciechowskaM, KrzyzosiakWJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 20: 3811–3821.

27. HsuRJ, HsiaoKM, LinMJ, LiCY, WangLC, et al. (2011) Long tract of untranslated CAG repeats is deleterious in transgenic mice. PLoS ONE 6: e16417 doi:10.1371/journal.pone.0016417.

28. WheelerTM, LueckJD, SwansonMS, DirksenRT, ThorntonCA (2007) Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117: 3952–3957.

29. FilippovaGN, ThienesCP, PennBH, ChoDH, HuYJ, et al. (2001) CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet 28: 335–343.

30. OrengoJP, WardAJ, CooperTA (2011) Alternative splicing dysregulation secondary to skeletal muscle regeneration. Ann Neurol 69: 681–690.

31. MuldersSA, van EngelenBG, WieringaB, WansinkDG (2010) Molecular therapy in myotonic dystrophy: focus on RNA gain-of-function. Hum Mol Genet 19: R90–97.

32. OrengoJP, CooperTA (2007) Alternative splicing in disease. Adv Exp Med Biol 623: 212–223.

33. CharizanisK, LeeKY, BatraR, GoodwinM, ZhangC, et al. (2012) Muscleblind-Like 2 Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy. Neuron 75: 437–450.

34. DuanC, RenH, GaoS (2010) Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. Gen Comp Endocrinol 167: 344–351.

35. Gomez-SaezJM, Fernandez-RealJM, NavarroMA, Martinez-MatosJA, SolerJ (1993) GH secretion status in myotonic dystrophy. Psychoneuroendocrinology 18: 183–190.

36. MoxleyRT, CorbettAJ, MinakerKL, RoweJW (1984) Whole body insulin resistance in myotonic dystrophy. Ann Neurol 15: 157–162.

37. HeatwoleCR, EichingerKJ, FriedmanDI, HilbertJE, JacksonCE, et al. (2011) Open-label trial of recombinant human insulin-like growth factor 1/recombinant human insulin-like growth factor binding protein 3 in myotonic dystrophy type 1. Arch Neurol 68: 37–44.

38. CoteC, HibaB, HebertLJ, VialC, RemecJF, et al. (2011) MRI of tibialis anterior skeletal muscle in myotonic dystrophy type 1. Can J Neurol Sci 38: 112–118.

39. PerseghinG, ComolaM, ScifoP, BenediniS, De CobelliF, et al. (2004) Postabsorptive and insulin-stimulated energy and protein metabolism in patients with myotonic dystrophy type 1. Am J Clin Nutr 80: 357–364.

40. PanaitePA, KielarM, KraftsikR, GourdonG, KuntzerT, et al. (2011) Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice. J Neuropathol Exp Neurol 70: 678–685.

41. HoltI, JacqueminV, FardaeiM, SewryCA, Butler-BrowneGS, et al. (2009) Muscleblind-like proteins: similarities and differences in normal and myotonic dystrophy muscle. Am J Pathol 174: 216–227.

42. HoeflichA, WuM, MohanS, FollJ, WankeR, et al. (1999) Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology 140: 5488–5496.

43. MetzgerF, SajidW, SaengerS, StaudenmaierC, van der PoelC, et al. (2011) Separation of fast from slow anabolism by site-specific PEGylation of insulin-like growth factor I (IGF-I). J Biol Chem 286: 19501–19510.

44. KisselevAF, GoldbergAL (2005) Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates. Methods Enzymol 398: 364–378.

45. CarrardG, DieuM, RaesM, ToussaintO, FriguetB (2003) Impact of ageing on proteasome structure and function in human lymphocytes. Int J Biochem Cell Biol 35: 728–739.

46. RidgleyJA, PinnigerGJ, HamerPW, GroundsMD (2009) The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice. Pflugers Arch 457: 1121–1132.

47. RocheJA, LoveringRM, BlochRJ (2008) Impaired recovery of dysferlin-null skeletal muscle after contraction-induced injury in vivo. Neuroreport 19: 1579–1584.

48. GorselinkM, DrostMR, de LouwJ, WillemsPJ, RosielleN, et al. (2000) Accurate assessment of in situ isometric contractile properties of hindlimb plantar and dorsal flexor muscle complex of intact mice. Pflugers Arch 439: 665–670.

49. MoyerM, BergerDS, LaddAN, Van LunterenE (2011) Differential susceptibility of muscles to myotonia and force impairment in a mouse model of myotonic dystrophy. Muscle Nerve 43: 818–827.

50. FuchtbauerEM, ReininghausJ, JockuschH (1988) Developmental control of the excitability of muscle: transplantation experiments on a myotonic mouse mutant. Proc Natl Acad Sci U S A 85: 3880–3884.

51. AgbulutO, VignaudA, HourdeC, MouiselE, FougerousseF, et al. (2009) Slow myosin heavy chain expression in the absence of muscle activity. Am J Physiol Cell Physiol 296: C205–214.

52. WardAJ, RimerM, KillianJM, DowlingJJ, CooperTA (2010) CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum Mol Genet 19: 3614–3622.

53. LinX, MillerJW, MankodiA, KanadiaRN, YuanY, et al. (2006) Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet 15: 2087–2097.

54. MankodiA, TakahashiMP, JiangH, BeckCL, BowersWJ, et al. (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10: 35–44.

55. FutatsugiA, KuwajimaG, MikoshibaK (1995) Tissue-specific and developmentally regulated alternative splicing in mouse skeletal muscle ryanodine receptor mRNA. Biochem J 305 (Pt 2)

373–378.