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Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type I spinal muscular atrophy

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Abstract

Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by the loss or mutation of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to the degeneration of motor neurons and muscular atrophy. In this study, we analyzed the nuclear reorganization in human skeletal myofibers from a type I SMA patient carrying a deletion of exons 7 and 8 in the SMN1 gene and two SMN2 gene copies and showing reduced SMN protein levels in the muscle compared with those in control samples. The morphometric analysis of myofiber size revealed the coexistence of atrophic and hypertrophic myofibers in SMA samples. Compared with controls, both nuclear size and the nuclear shape factor were significantly reduced in SMA myonuclei. Nuclear reorganization in SMA myonuclei was characterized by extensive heterochromatinization, the aggregation of splicing factors in large interchromatin granule clusters, and nucleolar alterations with the accumulation of the granular component and a loss of fibrillar center/dense fibrillar component units. These nuclear alterations reflect a severe perturbation of global pre-mRNA transcription and splicing, as well as nucleolar dysfunction, in SMA myofibers. Moreover, the finding of similar nuclear reorganization in both atrophic and hypetrophic myofibers provides additional support that the SMN deficiency in SMA patients may primarily affect the skeletal myofibers.

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References

  • Adriaens C, Serebryannyy LA, Feric M et al (2018) Blank spots on the map: some current questions on nuclear organization and genome architecture. Histochem Cell Biol 150:579–592

    Article  CAS  PubMed  Google Scholar 

  • Arnold AS, Gueye M, Guettier-Sigrist S, Courdier-Fruh I, Coupin G, Poindron P, Gies JP (2004) Reduced expression of nicotinic AchRs in myotubes from spinal muscular atrophy I patients. Lab Invest 84:1271–1278

    Article  CAS  PubMed  Google Scholar 

  • Biggiogera M, Burki K, Kaufmann SH, Shaper JH, Gas N, Almaric F et al (1990) Nucleolar distribution of proteins B23 and nucleolin in mouse preimplantation embryos as visualized by immunoelectron microscopy. Development 110:1263–1270

    CAS  PubMed  Google Scholar 

  • Biggiogera M, Cisterna B, Spedito A, Vecchio L, Malatesta M (2008) Perichromatin fibrils as early markers of transcriptional alterations. Differentiation 76:57–65

    Article  CAS  PubMed  Google Scholar 

  • Boyer JG, Ferrier A, Kothary R (2013) More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases. Frontiers Physiol 4:a356

    Article  Google Scholar 

  • Braun S, Croizat B, Lagrance MG, Warter JM, Poindron P (1995) Constitutive muscular abnormalities in culture in spinal muscular atrophy. Lancet 345:694–695

    Article  CAS  PubMed  Google Scholar 

  • Bricceno KV, Martinez T, Leikina E et al (2014) Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Gent 23:4745–4757

    Article  CAS  Google Scholar 

  • Burghes AH, Beattie CE (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 10:597–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burlet P, Huber C, Bertrandy S, Ludosky MA, Zwaenepoel I, Clermont O, Roume I, Delezoide AL, Cartaud J, Munnich A et al (1998) The distribution of the SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy. Hum Mol Genet 7:1927–1933

    Article  CAS  PubMed  Google Scholar 

  • Chaytow H, Huang Y-T, Gillingwater TH, Faller KME (2018) The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci 785:3877–3894

    Article  CAS  Google Scholar 

  • Cifuentes-Diaz C, Frugier T, Tiziano FD, Lacene E, Roblot N, Joshi V, Moreau MH, Melki J (2001) Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J Cell Biol 152:1107–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, Coulson SE, Androphy EJ, Prior TW, Burghes AH (1997) The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 6:1205–1214

    Article  CAS  PubMed  Google Scholar 

  • Dubowitz V, Sewry CA (2007) Muscle Biopsy. Practical Approach, Saunders-Elsevier

    Google Scholar 

  • Fidzianska A, Hausmanowa-Petrusewicz I (2003) Architectural abnormalities in muscle nuclei. Ultrastructural differences between X-linked and autosomal dominant forms of EDMD. J Neurol Sci 210:47–51

    Article  PubMed  Google Scholar 

  • Frugier T, Nicole S, Cifuentes-Diaz C, Melki J (2002) The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev 12:294–298

    Article  CAS  PubMed  Google Scholar 

  • Galganski L, Urbanek MO, Krzyzosiak WJ (2017) Nuclear speckles: molecular organization, biological functions and role in disease. Nucleic Acid Res 45:10350–10368

    Article  CAS  PubMed  Google Scholar 

  • Gall JG (2000) Cajal bodies: the first 100 years. Annu Rev Cell Dev Biol 16:273–300

    Article  CAS  PubMed  Google Scholar 

  • Gavrilov DK, Shi X, Das K, Gilliam TC, Wang CH (1998) Differential SMN2 expression associated with SMA severity. Nat Genet 20:230–231

    Article  CAS  PubMed  Google Scholar 

  • Groen EJN, Perenthaler E, Cortney NL et al (2018) Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy. Hum Mol Genet 27:2851–2862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guettier-Sigrist S, Hubel B, Coupin G, Freyssinet JM, Poindron P, Warter JM (2002) Possible pathogenic role of muscle cell dysfunction in motor neuron death in spinal muscular atrophy. Muscle Nerve 25:700–708

    Article  PubMed  Google Scholar 

  • Huang S, Spector DL (1996) Intron-dependent recruitment of pre-mRNA splicing factors to sites of transcription. J Cell Biol 131:719–732

    Article  Google Scholar 

  • Khatau SB, Hale CM, Stewart-Hutchinson PJ, Patel MS, Stewart CL, Searson PC, Hodzic D, Wirtz D (2009) A perinuclear actin cap regulates nuclear shape. Proc Natl Acad Sci USA 106:19017–19022

    Article  PubMed  Google Scholar 

  • Kolb SJ, Kissel JT (2011) Spinal muscular atrophy. Arch Neurol 68:979–984

    Article  PubMed  Google Scholar 

  • Kornblihtt AR, de la Mata M, Fededa JP, Muñoz MJ, Nogués G (2004) Multiple links between transcription and splicing. RNA 10:1489–1498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lafarga M, Tapia O, Romero AM, Berciano MT (2017) Cajal bodies in neurons. RNA Biol 14:712–725

    Article  PubMed  Google Scholar 

  • Lamond AI, Spector DL (2003) Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4:605–612

    Article  CAS  PubMed  Google Scholar 

  • Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, le Paslier D, Frézal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165

    Article  CAS  PubMed  Google Scholar 

  • Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, dreyfuss G, Melki J (1997) Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16:265–269

    Article  CAS  PubMed  Google Scholar 

  • Lemaitre C, Bickmore WA (2015) Chromatin at the nuclear periphery and the regulation of genome function. Histochem Cell Biol 144:111–122

    Article  CAS  PubMed  Google Scholar 

  • Lorson CL, Rindt H, Shababi M (2010) Spinal muscular atrophy. Mechanisms and therapeutic strategies. Hum Mol Genet 19:R111–R118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Machyna M, Heyn P, Neugebauer KM (2013) Cajal bodies: where form meets function. Wiley Interdiscip Rev RNA 4:17–34

    Article  CAS  PubMed  Google Scholar 

  • Maita R, Strauss M, Anselmi M (2009) Skeletal muscle for endomyocardial biopsy: comparable stress response in doxorubicin cardio-myopathy. J Toxicol Pathol 22:273–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Hernandez R, Soler-Botija C, Also E, Elias L, Caselles L, Gich I, Bernal S, Tizzano EF (2009) The developmental pattern of myotubes in spinal muscular atrophy indicates prenatal delay of muscle maturation. J Neuropathol Exp Neurol 68:474–481

    Article  PubMed  Google Scholar 

  • Masiello I, Siciliani S, Biggiogera M (2018) Perichromatin region: a moveable feast. Hitochem Cell Biol 150:227–233

    Article  CAS  Google Scholar 

  • Matera AG, Wang Z (2014) A day in the life of spliceosome. Nat Rev Mol Cell Biol 15:108–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melcák I, Melcácová S, Kopsky V, Vecerová J, Raska I (2001) Prespliceosomal assembly on microinjected precursor mRNA takes place in nuclear speckles. Mol Biol Cell 12:393–406

    Article  PubMed  PubMed Central  Google Scholar 

  • Mentis GZ, Blivis D, Liuy W, Drobac E, Crowder ME, Kong L, Alvarez FJ, Sumner CJ, O’Donovan MJ (2011) Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69:453–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monani UR (2005) Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48:885–896

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee RN, Chen P, Levy DL (2016) Recent advances in understanding nuclear size and shape. Nucleus 7:167–186

    Article  PubMed  PubMed Central  Google Scholar 

  • O’Keefe RT, Mayeda A, Sadowski CL, Krainer AR, Spector DL (1994) Disruption of pre-mRNA splicing in vivo results in reorganization of splicing factors. J Cell Biol 124:249–260

    Article  PubMed  Google Scholar 

  • Park Y-E, Hayashi YK, Goto K, Komaki H, Hayashi Y, Inuzuka T, Noguchi S, Nonaka I, Nishino I (2009) Nuclear changes in skeletal muscle extend to satellite cells in autosomal dominant Enery-Dreyfuss muscular dystrophy/limb-girdlemuscular dystrophy 1B. Neuromuscul Disord 19:29–36

    Article  PubMed  Google Scholar 

  • Pena E, Berciano MT, Fernandez R, Ojeda JL, Lafarga M (2001) Neuronal body size correlates with the number of nucleoli and Cajal bodies, and with the organization of splicing machinery in rat trigeminal ganglion neurons. J Comp Neurol 430:250–263

    Article  CAS  PubMed  Google Scholar 

  • Puckelwartz MJ, Kessler E, Zhang Y et al (2009) Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice. Hum Mol Genet 18:607–620

    Article  CAS  PubMed  Google Scholar 

  • Puvion-Dutilleul F, Mazan S, Nicoloso M, Pichard E, Bachellerie JP, Puvion E (1992) Alterations of nucleolar ultrastructure and ribosome biogenesis by actinomycin D. Implications for U3 snRNP function. Eur J Cell Biol 58:149–162

    CAS  PubMed  Google Scholar 

  • Rajendra TK, Gonsalvez GB, Walker MP, Shpargel KB, Salz HK, Matera AG (2007) A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol 176:831–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato S, Burgess SB, McIlwain DI (1994) Transcription and motoneuron size. J Neurochem 63:1609–1615

    Article  CAS  PubMed  Google Scholar 

  • Sewry CA, Brown SC, Mercuri E et al (2001) Skeletal muscle pathology in autosomal Emery-Dreyfuss muscular dystrophy with lamin A/C mutations. Neuropathol Appl Neurobiol 27:281–290

    Article  CAS  PubMed  Google Scholar 

  • Smirnov E, Cmarko D, Mazel T, Hornacek M, Raska I (2016) Nucleolar DNA: the host and the guests. Histochem Cell Biol 145:359–372

    Article  CAS  PubMed  Google Scholar 

  • Soler-Botija C, Ferrer I, Gich I, Baiget M, Tizzano EF (2002) Neuronal death is enhanced and begins during foetal development in type I spinal muscular atrophy spinal cord. Brain 125:1624–1634

    Article  PubMed  Google Scholar 

  • Stewart-Hutchinson PJ, Hale CM, Wirtz D, Hodzic D (2008) Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness. Exp Cell Res 14:1892–1905

    Article  CAS  Google Scholar 

  • Tapia O et al (2012) Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy. Histochem Cell Biol 137:657–667

    Article  CAS  PubMed  Google Scholar 

  • Tapia et al (2017) Cellular bases of the RNA metabolism dysfunction in motor neurons of a murine model of spinal muscular atrophy: role of Cajal bodies and nucleolus. Neurobiol Dis 108:83–99

    Article  CAS  PubMed  Google Scholar 

  • Van Steensel B, Belmont AS (2017) Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169:780–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker MP, Rajemdra TK, Saieva L, Fuentes JL, Pellizzoni L, Matera AG (2008) SMN complex localizes to sarcomeric Z-disc and is a proteolytic target of calpain. Hum Mol Genet 17:3399–3410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Reuveny A, Volk T (2015) Nesprin provide elastic properties to muscle nuclei by cooperating with spectraplakin and EB1. J Cell Biol 209:529–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Webster M, Witkin KL, Cohen-Fix O (2009) Sizing up the nucleus: nuclear shape, size and nuclear-envelope assembly. J Cell Sci 122:1477–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Raquel García-Ceballos for technical assistance. This work was supported by the following grants: “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED; CB06/05/0037) Spain, and “Instituto de Investigación Valdecilla” (IDIVAL, Next-Val), Spain.

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  1. María S. Castillo-Iglesias and María T. Berciano are co-first authors.

Authors and Affiliations

  1. Departamento de Anatomía y Biología Celular and “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)”, Universidad de Cantabria-IDIVAL, Avd. Cardenal Herrera Oria s/n, 39011, Santander, Spain

    María S. Castillo-Iglesias, J. Oriol Narcis, Olga Tapia & Miguel Lafarga

  2. Departamento de Biología Molecular, Universidad de Cantabria-IDIVAL, Santander, Spain

    María T. Berciano & José C. Rodriguez-Rey

  3. Unidad de Patología, Departamento de Ciencias Médicas y Quirúrgicas, Universidad de Cantabria-IDIVAL, Santander, Spain

    J. Fernando Val-Bernal

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  1. María S. Castillo-Iglesias
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Correspondence to Olga Tapia or Miguel Lafarga.

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Castillo-Iglesias, M.S., Berciano, M.T., Narcis, J.O. et al. Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type I spinal muscular atrophy. Histochem Cell Biol 152, 227–237 (2019). https://doi.org/10.1007/s00418-019-01792-6

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