Transcription factor REST dependent proteins are comparable between Down Syndrome and control brains: challenging a hypothesis

  • S. Y. Sohn
  • R. Weitzdoerfer
  • N. Mori
  • G. Lubec
Part of the Journal of Neural Transmission Supplement 67 book series (NEURAL SUPPL, volume 67)


Impairment of the RE-1-silencing transcription factor (REST) and REST — dependent genes in Down Syndrome (DS) neuronal progenitor cells and neurospheres has been published recently. As dysregulation of this system has been shown at the RNA level and considering the long and unpredictable way from RNA to proteins, and as it is the proteins that do the function in brain, we decided to test this hypothesis at the protein level.

Cortex of brains of patients with Down Syndrome at the early second trimester were used. REST — dependent structures as synapsin I, brain derived neurotrophic factor BDNF and neuronal growth-associated protein SCG10 were determined at the protein level using immunoblotting.

Proteins were comparably expressed in fetal Down syndrome and control brains. Even when normalized versus housekeeping genes (glyceraldehyde-6-phosphate-dehydrogenease) and a marker for neuronal density (neuron — specific enolase) DS results were resembling controls. Therefore, we cannot confirm the REST-hypothesis by our studies in the 18/19th week of gestation at the protein level in brain and taking into account that the hypothesis was based upon studies in progenitor cells.


Down Syndrome Down Syndrome Patient Silencer Element Repressor Element Silence Transcription 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. Antonsson B, Kassel DB, Di Paolo G, Lutjens R, Riederer BM, Grenningloh G (1998) Identification of in vitro phosphorylation sites in the growth cone protein SCG10. Effect of phosphorylation site mutants on microtubule-destabilizing activity. J Biol Chem 273: 8439–8446PubMedCrossRefGoogle Scholar
  2. Arai Y, Ijuin T, Takenawa T, Becker LE, Takashima S (2002) Excessive expression of synaptojanin in brains with Down syndrome. Brain Dev 24: 67–72PubMedCrossRefGoogle Scholar
  3. Bahn S, Mimmack M, Ryan M, Caldwell M, Jauniaux E, Starkey M, Svendsen C, Emson P (2002) Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down’s syndrome: a gene expression study. Lancet 359: 310–315PubMedCrossRefGoogle Scholar
  4. Bai G, Norton D, Prenger M, Kusiak J (1998) Single-stranded DNA-binding proteins and neuron-restrictive silencer factor participate in cell-specific transcriptional control of the NMDAR1 gene. J Biol Chem 273: 1086–1091PubMedCrossRefGoogle Scholar
  5. Becker L, Armstrong D, Chan F (1986) Dendritic atrophy in children with Down Syndrome. Ann Neurol 20: 520–526PubMedCrossRefGoogle Scholar
  6. Becker L, Mito T, Takashima S, Onodera K (1991) Growth and development of the brain in Down syndrome. Prog Clin Biol Res 373: 133–152PubMedGoogle Scholar
  7. Bessis A, Champtiaux N, Chatelin L, Changeux JP (1997) The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain. Proc Natl Acad Sci USA 94: 5906–5911PubMedCrossRefGoogle Scholar
  8. Brooksbank B, Walker D, Balasz R, Jorgensen OS (1989) Neuronal maturation in the foetal brain in Down’s syndrome. Early Hum Dev 18: 237–246PubMedCrossRefGoogle Scholar
  9. Chen ZF, Paquette A, Anderson D (1998) NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat Genet 20: 136–142PubMedCrossRefGoogle Scholar
  10. Cheon MS, Shim KS, Kim SH, Hara A, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis, part IV. Amino Acids 25: 41–47PubMedGoogle Scholar
  11. Chin LS, Li L, Ferreira A, Kosik K, Greengard P (1995) Impairment of axonal development and of synaptogenesis in hippocampal neurons of synapsin I-deficient mice. Proc Natl Acad Sci USA 92: 9230–9234PubMedCrossRefGoogle Scholar
  12. Chong JA, Tapia-Ramirez J, Kim S, Toledo-Aral J, Zheng Y, Boutros M, Altshuller Y, Frohman M, Kraner S, Mandel G (1995) REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 80: 949–957PubMedCrossRefGoogle Scholar
  13. Cowan J, Powers J, Tischler A (1996) Assignment of the REST gene to 4q12 by fluorescence in situ hybridization. Genomics 34: 260–262PubMedCrossRefGoogle Scholar
  14. Di Paolo G, Lutjens R, Osen-Sand A, Sobel A, Catsicas S, Grenningloh G (1997) Differential distribution of stathmin and SCG10 in developing neurons in culture. J Neurosci Res 50: 1000–1009PubMedCrossRefGoogle Scholar
  15. Engidawork E, Lubec G (2001) Protein expression in Down syndrome brain. Amino Acids 21: 331–361PubMedCrossRefGoogle Scholar
  16. Engidawork E, Lubec G (2003) Molecular changes in fetal Down Syndrome brain. J Neurochem 84: 895–904PubMedCrossRefGoogle Scholar
  17. Epstein C (1995) The metabolic and molecular bases of inherited disease. In: Scriver SR, Beaudet AL, Sly WS, Valle D (eds) Down Syndrome (Trisomy 21 ). McGraw Hill, New York, pp 749–794Google Scholar
  18. Ferreira A, Rapoport M (2002) The synapsins: beyond the regulation of neurotransmitter release. Cell Mol Life Sci 59: 589–595PubMedCrossRefGoogle Scholar
  19. Gulesserian T, Kim SH, Fountoulakis M, Lubec G (2002) Aberrant expression of centractin and capping proteins, integral constituents of the dynactin complex, in fetal Down syndrome brain. Biochem Biophys Res Commun 291: 62–67PubMedCrossRefGoogle Scholar
  20. Kallunki P, Edelman G, Jones F (1998) The neural restrictive silencer element can act as both a repressor and enhancer of L1 cell adhesion molecule gene expression during postnatal development. Proc Natl Acad Sci USA 95: 3233–3238PubMedCrossRefGoogle Scholar
  21. Kish S, Karlinsky H, Becker L, Gilbert J, Rebbetoy M, Chang LJ, DiStefano L, Hornykiewicz O (1989) Down’s syndrome individuals begin life with normal levels of brain cholinergic markers. J Neurochem 52: 1183–1187PubMedCrossRefGoogle Scholar
  22. Kraner SD, Chong JA, Tsay HJ, Mandel G (1992) Silencing the type II sodium channel gene: a model for neural-specific gene regulation. Neuron 9: 37–44PubMedCrossRefGoogle Scholar
  23. Li L, Suzuki T, Mori N, Greengard P (1993) Identification of a functional silencer element involved in neuron-specific expression of the synapsin I gene. Proc Natl Acad Sci USA 90: 1460–1464PubMedCrossRefGoogle Scholar
  24. Lubec B, Yoo BC, Dierssen M, Balic N, Lubec G (2001a) Down syndrome patients start early prenatal life with normal cholinergic, monoaminergic and serotoninergic innervation. J Neural Transm [Suppl] 61: 303–310Google Scholar
  25. Lubec B, Weitzdoerfer R, Fountoulakis M (2001b) Manifold reduction of moesin in fetal Down syndrome brain. Biochem Biophys Res Commun 286: 1191–1194PubMedCrossRefGoogle Scholar
  26. Lutjens R, Igarashi M, Pellier V, Blasey H, Di Paolo G, Ruchti E, Pfulg C, Staple JK, Catsicas S, Grenningloh G (2000) Localization and targeting of SCG10 to the trans-Golgi apparatus and growth cone vesicles. Eur J Neurosci 12: 2224–2234PubMedCrossRefGoogle Scholar
  27. Mason M, Lieberman A, Grenningloh G, Anderson P (2002) Transcriptional upregulation of SCG10 and CAP-23 is correlated with regeneration of the axons of peripheral and central neurons in vivo. Mol Cell Neurosci 20: 595PubMedCrossRefGoogle Scholar
  28. Mieda M, Haga T, Saffen D (1997) Expression of the rat m4 muscarinic acetylcholine receptor gene is regulated by the neuron-restrictive silencer element/repressor element 1. J Biol Chem 272: 5854–5860PubMedCrossRefGoogle Scholar
  29. Mori N, Schoenherr C, Vandenbergh D, Anderson D (1992) A common silencer element in the SCG10 and type II Na+ channel genes binds a factor present in nonneuronal cells but not in neuronal cells. Neuron 9: 45–54PubMedCrossRefGoogle Scholar
  30. Naruse Y, Aoki T, Kojima T, Mori N (1999) Neural restrictive silencer factor recruits mSin3 and histone deacetylase complex to repress neuron-specific target genes. Proc Natl Acad Sci USA 96: 13691–13696PubMedCrossRefGoogle Scholar
  31. Okazaki T, Wang H, Masliah E, Cao M, Johnson S, Sundsmo M, Saitoh T, Mori N (1995) SCG10, a neuron-specific growth-associated protein in Alzheimer’s disease. Neurobiol Aging 16: 883–894PubMedCrossRefGoogle Scholar
  32. Palm K, Belluardo N, Metsis M, Timmusk T (1998) Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J Neurosci 18: 1280–1296PubMedGoogle Scholar
  33. Paquette AJ, Perez SE, Anderson DJ (2000) Constitutive expression of the neuron-restrictive silencer factor ( NRSF)/REST in differentiating neurons disrupts neuronal gene expression and causes axon pathfinding errors in vivo. Proc Natl Acad Sci USA 97: 12318–12323PubMedCrossRefGoogle Scholar
  34. Pellier-Monnin V, Astic L, Bichet S, Riederer BM, Grenningloh G (2001) Expression of SCG10 and stathmin proteins in the rat olfactory system during development and axonal regeneration. J Comp Neurol 433: 239–254PubMedCrossRefGoogle Scholar
  35. Riederer BM, Pellier V, Antonsson B, Di Paolo G, Stimpson SA, Lutjens R, Catsicas S, Grenningloh G (1997) Regulation of microtubule dynamics by the neuronal growth-associated protein SCG10. Proc Natl Acad Sci USA 94: 741–745PubMedCrossRefGoogle Scholar
  36. Schoenherr CJ, Anderson DJ (1995) The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267: 1360–1363PubMedCrossRefGoogle Scholar
  37. Schoenherr CJ, Paquette AJ, Anderson DJ (1996) Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci USA 93: 9881–9886PubMedCrossRefGoogle Scholar
  38. Schoch S, Cibelli G, Thiel G (1996) Neuron-specific gene expression of synapsin I. Major role of a negative regulatory mechanism. J Biol Chem 271: 3317–3323PubMedCrossRefGoogle Scholar
  39. Schuman EM (1999) Neurotrophin regulation of synaptic transmission. Curr Opin Neurobiol 9: 105–109PubMedCrossRefGoogle Scholar
  40. Seth KA, Majzoub JA (2001) Repressor element silencing transcription factor/neuronrestrictive silencing factor ( REST/NRSF) can act as an enhancer as well as a repressor of corticotropin-releasing hormone gene transcription. J Biol Chem 276: 13917–13923PubMedGoogle Scholar
  41. Sugiura Y, Mori N (1995) SCG10 expresses growth-associated manner in developing rat brain, but shows a different pattern to p19/stathmin or GAP-43. Brain Res Dev Brain Res 90: 73–91PubMedCrossRefGoogle Scholar
  42. Thiel G, Lietz M, Leichter M (1999) Regulation of neuronal gene expression. Naturwissenschaften 86: 1–7PubMedCrossRefGoogle Scholar
  43. Timmusk T, Palm K, Lendahl U, Metsis M (1999) Brain-derived neurotrophic factor expression in vivo is under the control of neuron-restrictive silencer element. J Biol Chem 274: 1078–1084PubMedGoogle Scholar
  44. Weitzdoerfer R, Fountoulakis M, Lubec G (2002) Reduction of actin-related protein complex 2/3 in fetal Down syndrome brain. Biochem Biophys Res Commun 293: 836–841PubMedCrossRefGoogle Scholar
  45. 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
  46. Wisniewski K, Kida E (1994) Abnormal neurogenesis and synaptogenesis in Down Syndrome brain. Dev Brain Dysfunct 7: 289–301Google Scholar
  47. Wood IC, Roopra A, Buckley NJ (1996) Neural specific expression of the m4 muscarinic acetylcholine receptor gene is mediated by a RE1/NRSE-type silencing element. J Biol Chem 271: 14221–14225PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • S. Y. Sohn
    • 1
  • R. Weitzdoerfer
    • 2
  • N. Mori
    • 3
  • G. Lubec
    • 1
    • 4
  1. 1.Department of PediatricsUniversity of ViennaViennaAustria
  2. 2.Department of NeonatologyUniversity of ViennaViennaAustria
  3. 3.Department of Molecular Genetic ResearchNational Institute for Longevity SciencesOobu, AichiJapan
  4. 4.Department of PediatricsUniversity of ViennaViennaAustria

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