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Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells

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Abstract

Nurr1 is a transcription factor that is expressed in the embryonic ventral midbrain and is critical for the development of dopamine (DA) neurons. It belongs to the conserved family of nuclear receptors but lacks an identified ligand and is therefore referred to as an orphan receptor. Recent structural studies have indicated that Nurr1 belongs to a class of ligand-independent nuclear receptors that are unable to bind cognate ligands. However, Nurr1 can promote signaling via its heterodimerization partner, the retinoid X receptor (RXR). RXR ligands can promote the survival of DA neurons via a process that depends on Nurr1–RXR heterodimers. In developing DA cells, Nurr1 is required for the expression of several genes important for DA synthesis and function. However, Nurr1 is probably also important for the maintenance of adult DA neurons and plays additional less-well-elucidated roles in other regions of the central nervous system and in peripheral tissues.

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References

  • Arkenbout EK, Waard V de, Bragt M van, Achterberg TA van, Grimbergen JM, Pichon B, Pannekoek H, Vries CJ de (2002) Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation 106:1530–1535

    Article  CAS  PubMed  Google Scholar 

  • Arkenbout EK, Bragt M van, Eldering E, Bree C van, Grimbergen JM, Quax PH, Pannekoek H, Vries CJ de (2003) TR3 orphan receptor is expressed in vascular endothelial cells and mediates cell cycle arrest. Arterioscler Thromb Vasc Biol 23:1535–1540

    Article  CAS  PubMed  Google Scholar 

  • Backman C, Perlmann T, Wallén Å, Hoffer BJ, Morales M (1999) A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain. Brain Res 851:125–132

    Article  CAS  PubMed  Google Scholar 

  • Backman C, You ZB, Perlmann T, Hoffer BJ (2003) Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine. Behav Brain Res 143:95–100

    Article  CAS  PubMed  Google Scholar 

  • Bassett MH, Suzuki T, Sasano H, White PC, Rainey WE (2004) The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production. Mol Endocrinol 18:279–290

    Article  CAS  PubMed  Google Scholar 

  • Buervenich S, Carmine A, Arvidsson M, Xiang F, Zhang Z, Sydow O, Jonsson EG, Sedvall GC, Leonard S, Ross RG, Freedman R, Chowdari KV, Nimgaonkar VL, Perlmann T, Anvret M, Olson L (2000) NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Am J Med Genet 96:808–813

    Article  CAS  PubMed  Google Scholar 

  • Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, Nikodem VM (1998) Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol Cell Neurosci 11:36–46

    Article  CAS  PubMed  Google Scholar 

  • Castro DS, Hermanson E, Joseph B, Wallén Å, Aarnisalo P, Heller A, Perlmann T (2001) Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells. J Biol Chem 276:43277–43284

    Article  CAS  PubMed  Google Scholar 

  • Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294:1866–1870

    Article  CAS  PubMed  Google Scholar 

  • Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH (2002) Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 450:203–214

    Article  CAS  PubMed  Google Scholar 

  • Chung S, Sonntag KC, Andersson T, Bjorklund LM, Park JJ, Kim DW, Kang UJ, Isacson O, Kim KS (2002) Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Eur J Neurosci 16:1829–1838

    Article  PubMed  Google Scholar 

  • Crispino M, Tocco G, Feldman JD, Herschman HR, Baudry M (1998) Nurr1 mRNA expression in neonatal and adult rat brain following kainic acid-induced seizure activity. Brain Res Mol Brain Res 59:178–188

    Article  CAS  PubMed  Google Scholar 

  • Dunnett SB, Bjorklund A, Lindvall O (2001) Cell therapy in Parkinson’s disease—stop or go? Nat Rev Neurosci 2:365–369

    Article  CAS  PubMed  Google Scholar 

  • Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM (2002) Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res 136:267–275

    Article  CAS  PubMed  Google Scholar 

  • Falck B, Hillarp N-Å, Thieme G, Torp A (1962) Fluorescence of catechol amines and related compounds condensed with formaldehyde. J Histochem Cytochem 10:348–354

    CAS  Google Scholar 

  • Granholm AC, Reyland M, Albeck D, Sanders L, Gerhardt G, Hoernig G, Shen L, Westphal H, Hoffer B (2000) Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J Neurosci 20:3182–3190

    CAS  PubMed  Google Scholar 

  • Hering R, Petrovic S, Mietz EM, Holzmann C, Berg D, Bauer P, Woitalla D, Muller T, Berger K, Kruger R, Riess O (2004) Extended mutation analysis and association studies of Nurr1 (NR4A2) in Parkinson disease. Neurology 62:1231–1232

    Google Scholar 

  • Hermanson E, Joseph B, Castro D, Lindqvist E, Aarnisalo P, Wallén Å, Benoit G, Hengerer B, Olson L, Perlmann T (2003) Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells. Exp Cell Res 288:324–334

    Article  CAS  PubMed  Google Scholar 

  • Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C (1992) 9-cis Retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68:397–406

    Article  CAS  PubMed  Google Scholar 

  • Honkaniemi J, Sharp FR (1996) Global ischemia induces immediate-early genes encoding zinc finger transcription factors. J Cereb Blood Flow Metab 16:557–565

    Article  CAS  PubMed  Google Scholar 

  • Honkaniemi J, Sharp FR (1999) Prolonged expression of zinc finger immediate-early gene mRNAs and decreased protein synthesis following kainic acid induced seizures. Eur J Neurosci 11:10–17

    Article  CAS  PubMed  Google Scholar 

  • Honkaniemi J, Sagar SM, Pyykonen I, Hicks KJ, Sharp FR (1995) Focal brain injury induces multiple immediate early genes encoding zinc finger transcription factors. Brain Res Mol Brain Res 28:157–163

    Article  CAS  PubMed  Google Scholar 

  • Honkaniemi J, States BA, Weinstein PR, Espinoza J, Sharp FR (1997) Expression of zinc finger immediate early genes in rat brain after permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab 17:636–646

    Google Scholar 

  • Hynes M, Rosenthal A (1999) Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr Opin Neurobiol 9:26–36

    Article  CAS  PubMed  Google Scholar 

  • Hynes M, Porter JA, Chiang C, Chang D, Tessier-Lavigne M, Beachy PA, Rosenthal A (1995) Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15:33–44

    Article  Google Scholar 

  • Iwawaki T, Kohno K, Kobayashi K (2000) Identification of a potential Nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells. Biochem Biophys Res Commun 274:590–595

    Article  CAS  PubMed  Google Scholar 

  • Joseph B, Wallén-Mackenzie Å, Benoit G, Murata T, Joodmardi E, Okret S, Perlmann T (2003) p57(Kip2) cooperates with Nurr1 in developing dopamine cells. Proc Natl Acad Sci USA 100:15619–15624

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernuaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56

    Article  CAS  PubMed  Google Scholar 

  • Kim KS, Kim CH, Hwang DY, Seo H, Chung S, Hong SJ, Lim JK, Anderson T, Isacson O (2003a) Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell-specific manner. J Neurochem 85:622–634

    CAS  PubMed  Google Scholar 

  • Kim TE, Lee HS, Lee YB, Hong SH, Lee YS, Ichinose H, Kim SU, Lee MA (2003b) Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenptypes in the Nurr1-overexpressing neural stem cell. Biochem Biophys Res Commun 305:1040–1048

    Article  CAS  PubMed  Google Scholar 

  • Kliewer SA, Lehmann JM, Willson TM (1999) Orphan nuclear receptors: shifting endocrinology into reverse. Science 284:757–760

    Article  CAS  PubMed  Google Scholar 

  • Lammi J, Huppunen J, Aarnisalo P (2004) Regulation of the osteopontin gene by the orphan nuclear receptor Nurr1 in osteoblasts. Mol Endocrinol 18:1546–1557

    Article  Google Scholar 

  • Law SW, Conneely OM, DeMayo FJ, O’Malley BW (1992) Identification of a new brain-specific transcription factor, NURR1. Mol Endocrinol 6:2129–2135

    Article  CAS  PubMed  Google Scholar 

  • Le W, Conneely OM, He Y, Jankovic J, Appel SH (1999a) Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury. J Neurochem 73:2218–2221

    CAS  PubMed  Google Scholar 

  • Le W, Conneely OM, Zou L, He Y, Saucedo-Cardenas O, Jankovic J, Mosier DR, Appel SH (1999b) Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol 159:451–458

    Article  CAS  PubMed  Google Scholar 

  • Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, Vassilatis DK (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Jia H, Holmes DI, Stannard A, Zachary I (2003) Vascular endothelial growth factor-regulated gene expression in endothelial cells: KDR-mediated induction of Egr3 and the related nuclear receptors Nur77, Nurr1, and Nor1. Arterioscler Thromb Vasc Biol 23:2002–2007

    Article  CAS  PubMed  Google Scholar 

  • Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, et al (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839

    Article  CAS  PubMed  Google Scholar 

  • Mata de Urquiza A, Liu S, Sjöberg M, Zetterström RH, Griffiths W, Sjövall J, Perlmann T (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140–2144

    Article  CAS  PubMed  Google Scholar 

  • McEvoy AN, Bresnihan B, Fitzgerald O, Murphy EP (2002) Corticotropin-releasing hormone signaling in synovial tissue vascular endothelium is mediated through the cAMP/CREB pathway. Ann N Y Acad Sci 966:119–130

    CAS  PubMed  Google Scholar 

  • Murphy EP, McEvoy A, Conneely OM, Bresnihan B, FitzGerald O (2001) Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Arthritis Rheum 44:782–793

    Article  CAS  PubMed  Google Scholar 

  • Nsegbe E, Wallén-Mackenzie Å, Dauger S, Roux JC, Shvarev Y, Lagercrantz H, Perlmann T, Herlenius E (2004) Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice. J Physiol (Lond) 556:43–59

    Article  CAS  Google Scholar 

  • Ojeda V, Fuentealba JA, Galleguillos D, Andres ME (2003) Rapid increase of Nurr1 expression in the substantia nigra after 6-hydroxydopamine lesion in the striatum of the rat. J Neurosci Res 73:686–697

    Article  CAS  PubMed  Google Scholar 

  • Oo TF, Kholodilov N, Burke RE (2003) Regulation of natural cell death in dopaminergic neurons of the substantia nigra by striatal glial cell line-derived neurotrophic factor in vivo. J Neurosci 23:5141–5148

    CAS  PubMed  Google Scholar 

  • Ordentlich P, Yan Y, Zhou S, Heyman RA (2003) Identification of the anti-neoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 22:22

    Google Scholar 

  • Pena de Ortiz S, Jamieson GAJ (1996) GAJ HZF-3, an immediate-early orphan receptor homologous to Nurr1/NOT: induction upon membrane depolarization and seizures. Brain Res Mol Brain Res 38:1–13

    CAS  PubMed  Google Scholar 

  • Perlmann T, Jansson L (1995) A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9:769–782

    CAS  PubMed  Google Scholar 

  • Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J (1997) Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17:5946–5951

    Google Scholar 

  • Riddle R, Pollock JD (2003) Making connections: the development of mesencephalic dopaminergic neurons. Dev Brain Res 147:3–21

    Article  CAS  Google Scholar 

  • Sacchetti P, Brownschidle LA, Granneman JG, Bannon MJ (1999) Characterization of the 5′-flanking region of the human dopamine transporter gene. Brain Res Mol Brain Res 74:167–174

    Article  CAS  PubMed  Google Scholar 

  • Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ (2001) Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 76:1565–1572

    Article  CAS  PubMed  Google Scholar 

  • Sakurada K, Ohshima-Sakurada M, Palmer TD, Gage FH (1999) Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Development 126:4017–4026

    CAS  PubMed  Google Scholar 

  • Saucedo-Cardenas O, Conneely OM (1996) Comparative distribution of NURR1 and NUR77 nuclear receptors in the mouse central nervous system. J Mol Neurosci 7:51–63

    CAS  PubMed  Google Scholar 

  • Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, Burbach JP, Conneely OM (1998) Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 95:4013–4018

    Article  CAS  PubMed  Google Scholar 

  • Scearce LM, Laz TM, Hazel TG, Lau LF, Taub R (1993) RNR-1, a nuclear receptor in the NGFI-B/Nur77 family that is rapidly induced in regenerating liver. J Biol Chem 268:8855–8861

    CAS  PubMed  Google Scholar 

  • Simon HH, Saueressig H, Wurst W, Goulding MG, O’Leary DD (1998) En-1 and En-2 control the fate of the dopaminergic neurons in the substantia nigra and ventral tegmentum. Eur J Neurosci 10(Suppl 10):389

    Google Scholar 

  • Smidt MP, Schaick HS van, Lanctot C, Tremblay JJ, Cox JJ, Kleij AA van der, Wolterink G, Drouin J, Burbach JP (1997) A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 94:13305–13310

    Article  CAS  PubMed  Google Scholar 

  • Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP (2000) A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 3:337–341

    Article  CAS  PubMed  Google Scholar 

  • Smits SM, Ponnio T, Conneely OM, Burbach JP, Smidt MP (2003) Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons. Eur J Neurosci 18:1731–1738

    Article  PubMed  Google Scholar 

  • Sonntag KC, Simantov R, Kim KS, Isacson O (2004) Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation. Eur J Neurosci 19:1141–1152

    Google Scholar 

  • Tan EK, Chung H, Zhao Y, Shen H, Chandran VR, Tan C, Teoh ML, Yih Y, Pavanni R, Wong MC (2003) Genetic analysis of Nurr1 haplotypes in Parkinson’s disease. Neurosci Lett 347:139–142

    Article  CAS  PubMed  Google Scholar 

  • Thuret S, Bhatt L, O’Leary DD, Simon HH (2004) Identification and developmental analysis of genes expressed by dopaminergic neurons of the substantia nigra pars compacta. Mol Cell Neurosci 25:394–405

    Google Scholar 

  • Tseng KY, Roubert C, Do L, Rubinstein M, Kelly MA, Grandy DK, Low MJ, Gershanik OS, Murer MG, Giros B, Raisman-Vozari R (2000) Selective increase of Nurr1 mRNA expression in mesencephalic dopaminergic neurons of D2 dopamine receptor-deficient mice. Brain Res Mol Brain Res 80:1–6

    Article  CAS  PubMed  Google Scholar 

  • Ungerstedt U (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl 367:1–48

    CAS  PubMed  Google Scholar 

  • Wagner J, Akerud P, Castro DS, Holm PC, Canals JM, Snyder EY, Perlmann T, Arenas E (1999) Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. Nat Biotechnol 17:653–659

    Article  CAS  PubMed  Google Scholar 

  • Wallén Å, Zetterstrom RH, Solomin L, Arvidsson M, Olson L, Perlmann T (1999) Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice. Exp Cell Res 253:737–746

    Article  CAS  PubMed  Google Scholar 

  • Wallén Å, Castro DS, Zetterström RH, Karlén M, Olson L, Ericson J, Perlmann T (2001) Orphan nuclear receptor Nurr1 is essential for Ret expression in the midbrain dopamine neurons and in the brain stem. Mol Cell Neurosci 18:649–663

    Article  CAS  PubMed  Google Scholar 

  • Wallén-Mackenzie Å, Mata de Urquiza A, Petersson S, Rodriguez FJ, Friling S, Wagner J, Ordentlich P, Lengqvist J, Heyman RA, Arenas E, Perlmann T (2003) Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes Dev 17:3036–3047

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423:555–560

    Article  CAS  PubMed  Google Scholar 

  • Werme M, Hermanson E, Carmine A, Buervenich S, Zetterstrom RH, Thoren P, Ogren SO, Olson L, Perlmann T, Brene S (2003) Decreased ethanol preference and wheel running in Nurr1-deficient mice. Eur J Neurosci 17:2418–2424

    Google Scholar 

  • Witta J, Baffi JS, Palkovits M, Mezey E, Castillo SO, Nikodem VM (2000) Nigrostriatal innervation is preserved in Nurr1-null mice, although dopaminergic neuron precursors are arrested from terminal differentiation. Brain Res Mol Brain Res 84:67–78

    Article  CAS  PubMed  Google Scholar 

  • Wurst W, Bally-Cuif L (2001) Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci 2:99–108

    Article  CAS  PubMed  Google Scholar 

  • Xing G, Zhang L, Heynen T, Li XL, Smith MA, Weiss SR, Feldman AN, Detera-Wadleigh S, Chuang DM, Post RM (1997) Rat Nurr1 is prominently expressed in perirhinal cortex, and differentially induced in the hippocampal dentate gyrus by electroconvulsive vs. kindled seizures. Brain Res Mol Brain Res 47:251–261

    Article  CAS  PubMed  Google Scholar 

  • Zetterström RH, Solomin L, Mitsiadis T, Olson L, Perlmann T (1996a) Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Mol Endocrinol 10:1656–1666

    Article  PubMed  Google Scholar 

  • Zetterström RH, Williams R, Perlmann T, Olson L (1996b) Cellular expression of the immediate early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system. Brain Res Mol Brain Res 41:111–120

    PubMed  Google Scholar 

  • Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250

    Article  CAS  PubMed  Google Scholar 

  • Zhou QY, Palmiter RD (1995) Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83:1197–1209

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Gerard Benoit for the preparation of Fig. 1. This work as supported by Swedish Foundation for Strategic Research and the Wallenberg Foundation.

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  1. The Ludwig Institute, Stockholm, Sweden

    Thomas Perlmann & Åsa Wallén-Mackenzie

  2. Department of Cell and Molecular Biology, Karolinska Institutet, Box 240, 171 77, Stockholm, Sweden

    Thomas Perlmann

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Correspondence to Thomas Perlmann.

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Perlmann, T., Wallén-Mackenzie, Å. Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells. Cell Tissue Res 318, 45–52 (2004). https://doi.org/10.1007/s00441-004-0974-7

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