Downregulation of the transcription factor scleraxis in brain of patients with Down Syndrome

  • K. Yeghiazaryan
  • D. Turhani-Schatzmann
  • O. Labudova
  • E. Schuller
  • E. N. Olson
  • N. Cairns
  • G. Lubec
Conference paper


Performing gene hunting in fetal Down Syndrome (DS) brain, we found a downregulated sequence with 100% homology to the basic — helix — loop — helix transcription factor (TF) scleraxis (Scl).

It was the aim of the study to evaluate Scl — mRNA steady state levels in adult DS brain with Alzheimer’s disease (AD) neuropathological changes, brain of patients with AD, and controls in order to find out whether Scl — downregulation is linked to DS per se or simply to neurodegeneration, common to both disorders.

Determination of Scl — mRNA steady state levels was carried out by a blotting method in frontal, parietal, temporal, occipital lobe and cerebellum.

We found significantly decreased Scl — transcripts in brain of DS and AD, both, when normalized versus the house-keeping gene beta actin or total RNA.

We demonstrate the significant decrease of Scl — mRNA steady state levels in the pathogenesis of DS and AD suggesting a tentative role for this transcription factor in the development of the neurodegenerative processes known to occur in both disorders. More specifically, the biological meaning of the downregulation of Scl may be the involvement in the pathogenesis of impaired neuronal plasticity and wiring observed in DS and AD, phenomena regulated by the concerted action of the many transcription factors expressed in human brain.


Down Syndrome Slot Blot Helix Transcription Factor Type Transcription Factor Down Syndrome Brain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adams MD, Kelley JM, Gocayne JD, Dubnick M, Polymeropoulos MH, Xiao H, Merril CR, Wu A, Olde BO, Moreno RF, Kerlavage AR, McCombie WR, Venter JC (1991) Complementary DNA sequencing: expressed sequence tags and human genome project. Science 252: 1651–1656PubMedCrossRefGoogle Scholar
  2. Adams MD, Dubnick M, Kerlavage AR, Moreno R, Kelley JM, Utterback RT, Nagle JW, Fields C, Venter JC (1992) Sequence identification of 2,375 human brain genes. Nature 355: 632–634PubMedCrossRefGoogle Scholar
  3. Arenander AT, De Vellis J (1994) Development of the nervous system. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff PB (eds) Basic neurochemistry, 5th edn. Raven Press, New York, pp 573–606Google Scholar
  4. Burger PC, Vogel FS (1973) The development of pathologic changes of Alzheimer’s disease and senile dementia in patients with Down’s syndrome. Am J Pathol 73: 457–476PubMedGoogle Scholar
  5. Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 378: 776–779PubMedCrossRefGoogle Scholar
  6. Cserjesi P, Brown D, Ligon KL, Lyons GE, Copeland NG, Gilbert DJ, Jenkins NA, Olson EN (1995) Scleraxis: a basic helix-loop-helix protgein that prefigures skeletal formation during mouse embryogenesis. Development 121: 1099–1110PubMedGoogle Scholar
  7. Epstein CJ (1992) Down Syndrome (Trisomy 21) In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw Hill, New York, pp 749–794Google Scholar
  8. Fang-Kircher S, Labudova O, Kitzmueller E, Rink H, Cairns N, Lubec G (1999) Increased steady state mRNA levels of DNA repair genes XRCC1, ERCC2 and ERCC3 in brain of patients with Down Syndrome. Life Sci (in press)Google Scholar
  9. Hardmeier R, Hoeger H, Fang-Kircher S, Khoshsorur A, Lubec G (1997) Transcription and activity of superoxide dismutase, catalase and glutathione peroxidase following irradiation in radiation resistant and radiation sensitive mice Proc. Natl Acad Sci (USA) 94: 7572–7576CrossRefGoogle Scholar
  10. He X, Rosenfeld MG (1991) Mechanisms of complex transcriptional regulation: implications for brain development. Neuron 7: 183–196PubMedCrossRefGoogle Scholar
  11. Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE (1997) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase — 3 family protease. Science 277: 373–376PubMedCrossRefGoogle Scholar
  12. Kitamura Y, Shimohama S, Kamoshima W, Ota T, Matsuoka Y, Nomura Y, Smith MA, Perry G, Whithouse PJ, Taniguchi T (1998) Alteration of proteins regulating apoptosis, bcl-2, bcll-x, bax, bak, bad, ICH-1 and CPP32 in Alzheimer’s disease. Brain Res 780: 260–269PubMedCrossRefGoogle Scholar
  13. Kola I, Christiano F, de Haan JB, Thomas R, Sumarsono S, Corrick CM, Tymms M (1995) Genes, embryogenesis and Down Syndrome. In: Moeloek FA, Affandi B, Trounson AO (eds) Advances in human reproduction. Casterton-Parthenon, NY, pp 309–320Google Scholar
  14. Labudova O, Lubec G (1998) cAMP upregulates the transposable element mys-1: a possible link between signaling and mobile DNA. Life Sci 62: 431–437PubMedCrossRefGoogle Scholar
  15. Labudova O, Fang-Kircher S, Cairns N, Lubec G (1998) Upregulation of vasopressin in brain of patients with Down Syndrome. Brain Res 806: 55–59PubMedCrossRefGoogle Scholar
  16. Labudova O, Krapfenbauer K, Moenkemann H, Rink H, Kitzmueller E, Cairns N, Lubec G (1998) Decreased transcription factor junD in brain of patients with Down Syndrome. Neurosci Lett 252: 159–162PubMedCrossRefGoogle Scholar
  17. Liu Y, Cserjesi P, Nifuji A, Olson EN, Noda M (1996) Sclerotome-related helix-loop-helix type transcription factor (scleraxis) mRNA is expressed in osteoblasts and its level is enhanced by type-beta transforming growth factor. J Endocrinol 151: 491–499PubMedCrossRefGoogle Scholar
  18. Liu Y, Nifuji A, Tamura M, Wozney JM, Olson EN, Noda M (1997) Scleraxis messenger ribonucleic acid is expressed in C2C12 myoblasts and its level is down-regulated by bone morphogenetic protein’ 2 (BMP2). J Cell Biochem 67: 66–74PubMedCrossRefGoogle Scholar
  19. Liu Y, Watanabe H, Nifuji A, Yamada Y, Olson EN, Noda M (1997) Overexpression of a single helix-loop-helix type transcription factor, scleraxis, enhances aggrecan gene expression in osteoblastic osteosarcoma ROS17/2.8 cells. J Biol Chem 272: 29880–29885PubMedCrossRefGoogle Scholar
  20. Ma L, Westbroek A, Jochemsen AG, Weeda G, Bosch A, Bootsma D, Hoeijmakers JHJ, van der Erb AJ (1994) Mutational analysis of ERCC3, which is involved in DNA repair and transcription initiation: identification of domains essential for the DNA repair function. Mol Cell Biol 14: 4126–4134PubMedGoogle Scholar
  21. McMaster GK, Carmichael GG (1977) Analysis by single and double stranded nucleic acids on Polyacrylamide and agarose gels by using glyoxal and acridine orange. Proc Natl Acad Sci (USA) 74: 4835–4841CrossRefGoogle Scholar
  22. Mirra SS, Heyman A, McKeel D, Sumi S, Crain BJ (1991) The consortium to establish a registry for Alzheimer disease (CERAD). II. Standardisation of the neuropathologi-cal assessment of Alzheimer’s disease. Neurology 41: 479–486PubMedCrossRefGoogle Scholar
  23. Morris BJ (1997) Neuronal plasticity. In: Davies RW, Morris BJ (eds) Molecular biology of the neuron. Bios Scientifique Publishers, Oxford, pp 323–335Google Scholar
  24. Nagy ZS, Esiri MM (1997) Apoptosis — related protein expression in the hippocampus in Alzheimer’s disease. Neurobiol Aging 18: 565–571PubMedCrossRefGoogle Scholar
  25. Schaeffer L, Moncollin V, Roy R, Staub A, Mezzina M, Sarasin A, Weeda G, Hoeijmakers JHJ, Egly JM (1994) The ERCC2 / DNA repair protein is associated with the class II BTF2 / TFIIH transcription factor. EMBO J 13: 2388–2392PubMedGoogle Scholar
  26. Seidl R, Greber S, Schuller E, Bernert G, Cairns N, Lubec G (1997) Evidence against increased oxidative DNA damage in Down Syndrome. Neurosci Lett 235: 137–140PubMedCrossRefGoogle Scholar
  27. Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98: 503–511PubMedCrossRefGoogle Scholar
  28. Tierney MC, Fisher RH, Lewis AJ, Torzitto ML, Snow WG, Reid DW, Nieuwstraaten P, Van Rooijen LAA, Derks HJGM, Van Wijk R, Bischop A (1988) The NINCDA-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer’s disease. Neurology 38: 359–364PubMedCrossRefGoogle Scholar
  29. Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupoid SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmakers JHJ, Harris CC (1996) The XPB and XPD DNA helicases are components of the p53 mediated apoptosis pathway. Genes Dev 10: 1219–1232PubMedCrossRefGoogle Scholar
  30. Warbrick E (1996) Apoptosis: a new twist to the tale? Curr Biol 6: 1057–1059PubMedCrossRefGoogle Scholar
  31. White BA, Bancroft FC (1982) Cytoplasmic dot hybridization. Simple analysis of mRNA levels in multiple small cell or tissue samples. J Biol Chem 257: 8569–8574PubMedGoogle Scholar
  32. Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1999

Authors and Affiliations

  • K. Yeghiazaryan
    • 1
  • D. Turhani-Schatzmann
    • 1
  • O. Labudova
    • 2
  • E. Schuller
    • 1
  • E. N. Olson
    • 3
  • N. Cairns
    • 4
  • G. Lubec
    • 1
  1. 1.Department of PediatricsUniversity of ViennaViennaAustria
  2. 2.Department of RadiobiologyUniversity of BonnFederal Republic of Germany
  3. 3.Southwestern Medical CenterUniversity of TexasDallasUSA
  4. 4.Institute of PsychiatryBrain BankLondonUK

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