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Table of Contents
Vol. 1, No. 6, 2004
Issue release date: May 2005
Section title: Original Paper
Neurodegenerative Dis 2004;1:255–265
(DOI:10.1159/000085064)

Influence of Different Promoters on the Expression Pattern of Mutated Human α-Synuclein in Transgenic Mice

Maskri L.a · Zhu X.a · Fritzen S.a · Kühn K.a · Ullmer C.b · Engels P.b · Andriske M.a · Stichel C.C.b · Lübbert H.a,b
aAnimal Physiology, Ruhr University Bochum, Bochum and bBiofrontera Pharmaceuticals GmbH, Leverkusen, Germany
email Corresponding Author

Abstract

Two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein α-synuclein (asyn) are associated with rare, dominantly inherited forms of Parkinson’s disease (PD) and its accumulation in Lewy bodies and Lewy neurites. As an initial step in investigating the role of asyn in the pathogenesis of PD, we have generated C57BL/6 transgenic mice overexpressing the doubly mutated human asyn under the control of three different promoters; the chicken β-actin (chβactin), the mouse tyrosine hydroxylase 9.6 kb (msTH) and the mouse prion protein (msprp). In this study we compared the regional and cellular expression pattern of the transgenic protein in the brain and peripheral organs of various transgenic mouse lines. Western blot analysis and immunohistochemistry consistently showed that all three promoters successfully drive the expression of the transgene. The msprp promoter was found to give the highest level of transgene expression. All promoters directed the expression into the brain and specific neuron types. However, the promoters differed with respect to (i) the expression pattern in peripheral organs, (ii) the number and (iii) the regional distribution of expressing cells in the brain. Furthermore, remarkable line-to-line variation of expression patterns was observed in mouse lines carrying the same construct. Future studies will analyze how the variations in transgene expression affect the pathogenesis in the animals.

© 2004 S. Karger AG, Basel


  

Key Words

  • Parkinson’s disease
  • Promoter activity
  • Nigrostriatal system
  • α-Synuclein
  • Transgene

References

  1. Maroteaux L, Campanelli JT, Scheller RH: Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 1988;8:2804–2815.
  2. Clayton DF, George JM: The synucleins: A family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 1998;21:249–254.
  3. George JM: The synucleins. Genome Biol 2002;3:S3002.
  4. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Rohan de Silva HA, Kittel A, Saitoh T: The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995;14:467–475.
  5. Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC: Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science 1996;274:1197–1199.
  6. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047.
  7. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O: Ala30 Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 1998;18:106–108.
  8. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez TE, del Ser T, Munoz DG, De Yebenes JG: The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164–173.
  9. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K: α-Synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841.
  10. Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M: α-Synuclein in Lewy bodies. Nature 1997;388:339–340.

    External Resources

  11. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H: NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci Lett 1997;239:45–48.
  12. Krüger R, Menezes Vieira-Saecker AM, Kuhn W, Berg D, Müller T, Kühnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schöls L, Riess O: Increased susceptibility to sporadic Parkinson’s disease by a certain combined α-synuclein/apolipoprotein E genotype. Ann Neurol 1999;45:611–617.
  13. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM: Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 2002;34:521–533.
  14. Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C: Subcellular localization of wild-type and Parkinson’s disease-associated mutant α-synuclein in human and transgenic mouse brain. J Neurosci 2000;20:6365–6373.
  15. Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL: Human α-synuclein-harboring familial Parkinson’s disease-linked Ala- 53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 2002;99:8968–8973.
  16. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L: Dopaminergic loss and inclusion body formation in α-synuclein mice: Implications for neurodegenerative disorders. Science 2000;287:1265–1269.
  17. Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte D: Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001;8:535–539.
  18. Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, Schulz JB: Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α-synuclein transgenic mice. J Neurochem 2001;77:1181–1184.
  19. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ: Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp Neurol 2002;175:35–48.
  20. Van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G: Neuropathology in mice expressing human α-synuclein. J Neurosci 2000;20:6021–6029.
  21. Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E: Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002;68:568–578.
  22. Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH: Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. Neurobiol Aging 2003;24:245–258.
  23. Gispert S, Del Turco D, Garrett L, Chen A, Bernard D J, Hamm-Clement J, Korf H W, Deller T, Braak H, Auburger G, Nussbaum RL: Transgenic mice expressing mutant A53T human α-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 2003;24:419–429.
  24. Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK: Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur J Neurosci 2004;19:845–854.
  25. Neuhoff VPK, Zimmer HG, Mesecke S: A simple and versatile, sensitive and volume-independent method for quantitative protein determination with independence of other external influences. Hoppe Seylers Z Physiol Chem 1979;360:1657–1670.
  26. Stichel CC, Singer W, Zilles K: Ultrastructure of PkC(II/III)-immunopositive structures in rat primary visual cortex. Exp Brain Res 1990;82:575–584.
  27. Paxinos G, Franklin KBJ, The Mouse Brain in Stereotaxic Coordinates. San Diego, Academic Press, 2001.
  28. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH: Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 1995;95:1446–1456.
  29. Ho YS: Transgenic and knockout models for studying the role of lung antioxidant enzymes in defense against hyperoxia. Am J Respir Crit Care Med 2002;166:S51–S56.

    External Resources

  30. Kosuga M, Enosawa S, Li XK, Suzuki S, Matsuo N, Yamada M, Roy-Chowdhury J, Koiwai O, Okuyama T: Strong, long-term transgene expression in rat liver using chicken β-actin promoter associated with cytomegalovirus immediate-early enhancer (CAG promoter). Cell Transplant 2000;9:675–680.
  31. Seng S, Yokoyama M, Suzuki R, Maki Y, Kato M, Lim C, Zayatiin B, Inoue N, Xuan X, Igarashi I, Nagasawa H, Fujisaki K, Mikami T, Suzuki N, Toyoda Y: Expression of SAG-1 of Toxoplasma gondii in transgenic mice. Parasitol Res 2000;86:263–269.
  32. Manson J, West JD, Thomson V, McBride P, Kaufman MH, Hope J: The prion protein gene: A role in mouse embryogenesis? Development 1992;115:117–122.
  33. Ford MJ, Burton LJ, Morris RJ, Hall SM: Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 2002;113:177–192.
  34. Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL: A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 1996;13:159–163.
  35. Liu T, Zwingmann T, Li R, Pan T, Wong BS, Petersen RB, Gambetti P, Herrup K, Sy MS: Differential expression of cellular prion protein in mouse brain as detected with multiple anti-PrP monoclonal antibodies. Brain Res 2001;896:118–129.
  36. Kaech S, Fischer M, Doll T, Matus A: Isoform specificity in the relationship of actin to dendritic spines. J Neurosci 1997;17:9565–9572.
  37. Schimmel JJ, Crews L, Roffler-Tarlov S, Chikaraishi DM: 4.5 kb of the rat tyrosine hydroxylase 5′-flanking sequence directs tissue-specific expression during development and contains consensus sites for multiple transcription factors. Mol Brain Res 1999;74:1–14.
  38. Banerjee SA, Roffler-Tarlov S, Szabo M, Frohman L, Chikaraishi DM: DNA regulatory sequences of the rat tyrosine hydroxylase gene direct correct catecholaminergic cell-type specificity of a human growth hormone reporter in the CNS of transgenic mice causing a dwarf phenotype. Mol Brain Res 1994;24:89–106.
  39. Son JH, Min N, Joh TH: Early ontogeny of catecholaminergic cell lineage in brain and peripheral neurons monitored by tyrosine hydroxylase-lacZ transgene. Brain Res Mol Brain Res 1996;36:300–308.
  40. Min N, Joh TH, Kim KS, Peng C, Son JH: 5′ upstream DNA sequence of the rat tyrosine hydroxylase gene directs high-level and tissue-specific expression to catecholaminergic neurons in the central nervous system of transgenic mice. Brain Res Mol Brain Res 1994;27:281–289.
  41. Moser M, Colello RJ, Pott U, Oesch B: Developmental expression of the prion protein gene in glial cells. Neuron 1995;14:509–517.
  42. Verghese-Nikolakaki S, Michaloudi H, Polymenidou M, Groschup MH, Papadopoulos GC, Sklaviadis T: Expression of the prion protein in the rat forebrain – An immunohistochemical study. Neurosci Lett 1999;272:9–12.
  43. Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, Smithies O: Single-copy transgenic mice with chosen-site integration. Proc Natl Acad Sci USA 1996;93:9067–9072.
  44. Andrä K, Abramowski D, Duke M, Probst A, Wiederhold K-H, Bürki K, Goedert M, Sommer B, Staufenbiel M: Expression of APP in transgenic mice: A comparison of neuron-specific promoters. Neurobiol Aging 1996;17:183–190.

  

Author Contacts

Christine C. Stichel, PhD
Animal Physiology, Biology, ND5/132
Ruhr University Bochum
DE–44780 Bochum (Germany)
Tel. +49 234 3225829, Fax +49 234 3214189, E-Mail c.stichel-gunkel@biofrontera.com

  

Article Information

L.M. and X.Z. both contributed equally.

Received: July 7, 2004
Accepted after revision: November 14, 2004
Number of Print Pages : 11
Number of Figures : 5, Number of Tables : 1, Number of References : 44

  

Publication Details

Neurodegenerative Diseases

Vol. 1, No. 6, Year 2004 (Cover Date: Released May 2005)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


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References

  1. Maroteaux L, Campanelli JT, Scheller RH: Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 1988;8:2804–2815.
  2. Clayton DF, George JM: The synucleins: A family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 1998;21:249–254.
  3. George JM: The synucleins. Genome Biol 2002;3:S3002.
  4. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, Rohan de Silva HA, Kittel A, Saitoh T: The precursor protein of non-Aβ component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995;14:467–475.
  5. Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC: Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science 1996;274:1197–1199.
  6. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL: Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045–2047.
  7. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O: Ala30 Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 1998;18:106–108.
  8. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez TE, del Ser T, Munoz DG, De Yebenes JG: The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164–173.
  9. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K: α-Synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841.
  10. Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M: α-Synuclein in Lewy bodies. Nature 1997;388:339–340.

    External Resources

  11. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H: NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci Lett 1997;239:45–48.
  12. Krüger R, Menezes Vieira-Saecker AM, Kuhn W, Berg D, Müller T, Kühnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schöls L, Riess O: Increased susceptibility to sporadic Parkinson’s disease by a certain combined α-synuclein/apolipoprotein E genotype. Ann Neurol 1999;45:611–617.
  13. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM: Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 2002;34:521–533.
  14. Kahle PJ, Neumann M, Ozmen L, Müller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C: Subcellular localization of wild-type and Parkinson’s disease-associated mutant α-synuclein in human and transgenic mouse brain. J Neurosci 2000;20:6365–6373.
  15. Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL: Human α-synuclein-harboring familial Parkinson’s disease-linked Ala- 53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 2002;99:8968–8973.
  16. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L: Dopaminergic loss and inclusion body formation in α-synuclein mice: Implications for neurodegenerative disorders. Science 2000;287:1265–1269.
  17. Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte D: Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001;8:535–539.
  18. Rathke-Hartlieb S, Kahle PJ, Neumann M, Ozmen L, Haid S, Okochi M, Haass C, Schulz JB: Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α-synuclein transgenic mice. J Neurochem 2001;77:1181–1184.
  19. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ: Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp Neurol 2002;175:35–48.
  20. Van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G: Neuropathology in mice expressing human α-synuclein. J Neurosci 2000;20:6021–6029.
  21. Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, Masliah E: Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res 2002;68:568–578.
  22. Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S, Sondel J, Kotilinek L, Day J, Schwarzschild MA, Cha JH, Newell K, Miller DW, Ueda K, Young AB, Hyman BT, Ashe KH: Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. Neurobiol Aging 2003;24:245–258.
  23. Gispert S, Del Turco D, Garrett L, Chen A, Bernard D J, Hamm-Clement J, Korf H W, Deller T, Braak H, Auburger G, Nussbaum RL: Transgenic mice expressing mutant A53T human α-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol Cell Neurosci 2003;24:419–429.
  24. Thiruchelvam MJ, Powers JM, Cory-Slechta DA, Richfield EK: Risk factors for dopaminergic neuron loss in human α-synuclein transgenic mice. Eur J Neurosci 2004;19:845–854.
  25. Neuhoff VPK, Zimmer HG, Mesecke S: A simple and versatile, sensitive and volume-independent method for quantitative protein determination with independence of other external influences. Hoppe Seylers Z Physiol Chem 1979;360:1657–1670.
  26. Stichel CC, Singer W, Zilles K: Ultrastructure of PkC(II/III)-immunopositive structures in rat primary visual cortex. Exp Brain Res 1990;82:575–584.
  27. Paxinos G, Franklin KBJ, The Mouse Brain in Stereotaxic Coordinates. San Diego, Academic Press, 2001.
  28. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH: Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 1995;95:1446–1456.
  29. Ho YS: Transgenic and knockout models for studying the role of lung antioxidant enzymes in defense against hyperoxia. Am J Respir Crit Care Med 2002;166:S51–S56.

    External Resources

  30. Kosuga M, Enosawa S, Li XK, Suzuki S, Matsuo N, Yamada M, Roy-Chowdhury J, Koiwai O, Okuyama T: Strong, long-term transgene expression in rat liver using chicken β-actin promoter associated with cytomegalovirus immediate-early enhancer (CAG promoter). Cell Transplant 2000;9:675–680.
  31. Seng S, Yokoyama M, Suzuki R, Maki Y, Kato M, Lim C, Zayatiin B, Inoue N, Xuan X, Igarashi I, Nagasawa H, Fujisaki K, Mikami T, Suzuki N, Toyoda Y: Expression of SAG-1 of Toxoplasma gondii in transgenic mice. Parasitol Res 2000;86:263–269.
  32. Manson J, West JD, Thomson V, McBride P, Kaufman MH, Hope J: The prion protein gene: A role in mouse embryogenesis? Development 1992;115:117–122.
  33. Ford MJ, Burton LJ, Morris RJ, Hall SM: Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 2002;113:177–192.
  34. Borchelt DR, Davis J, Fischer M, Lee MK, Slunt HH, Ratovitsky T, Regard J, Copeland NG, Jenkins NA, Sisodia SS, Price DL: A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 1996;13:159–163.
  35. Liu T, Zwingmann T, Li R, Pan T, Wong BS, Petersen RB, Gambetti P, Herrup K, Sy MS: Differential expression of cellular prion protein in mouse brain as detected with multiple anti-PrP monoclonal antibodies. Brain Res 2001;896:118–129.
  36. Kaech S, Fischer M, Doll T, Matus A: Isoform specificity in the relationship of actin to dendritic spines. J Neurosci 1997;17:9565–9572.
  37. Schimmel JJ, Crews L, Roffler-Tarlov S, Chikaraishi DM: 4.5 kb of the rat tyrosine hydroxylase 5′-flanking sequence directs tissue-specific expression during development and contains consensus sites for multiple transcription factors. Mol Brain Res 1999;74:1–14.
  38. Banerjee SA, Roffler-Tarlov S, Szabo M, Frohman L, Chikaraishi DM: DNA regulatory sequences of the rat tyrosine hydroxylase gene direct correct catecholaminergic cell-type specificity of a human growth hormone reporter in the CNS of transgenic mice causing a dwarf phenotype. Mol Brain Res 1994;24:89–106.
  39. Son JH, Min N, Joh TH: Early ontogeny of catecholaminergic cell lineage in brain and peripheral neurons monitored by tyrosine hydroxylase-lacZ transgene. Brain Res Mol Brain Res 1996;36:300–308.
  40. Min N, Joh TH, Kim KS, Peng C, Son JH: 5′ upstream DNA sequence of the rat tyrosine hydroxylase gene directs high-level and tissue-specific expression to catecholaminergic neurons in the central nervous system of transgenic mice. Brain Res Mol Brain Res 1994;27:281–289.
  41. Moser M, Colello RJ, Pott U, Oesch B: Developmental expression of the prion protein gene in glial cells. Neuron 1995;14:509–517.
  42. Verghese-Nikolakaki S, Michaloudi H, Polymenidou M, Groschup MH, Papadopoulos GC, Sklaviadis T: Expression of the prion protein in the rat forebrain – An immunohistochemical study. Neurosci Lett 1999;272:9–12.
  43. Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, Smithies O: Single-copy transgenic mice with chosen-site integration. Proc Natl Acad Sci USA 1996;93:9067–9072.
  44. Andrä K, Abramowski D, Duke M, Probst A, Wiederhold K-H, Bürki K, Goedert M, Sommer B, Staufenbiel M: Expression of APP in transgenic mice: A comparison of neuron-specific promoters. Neurobiol Aging 1996;17:183–190.