TABLE 21

NURR1

Receptor nomenclature NR4A2
Receptor code 4.10.1:OR:4:A2
Other names NOT, TINUR, HZF-3, RNR-1, NGFI-Bβ
Molecular information Hs: 598aa, P43354, chr. 2q241
Rn: 598aa, Q07917, chr. 3q122
Mm: 598aa, Q06219, chr. 2 C23
DNA binding
   Structure Monomer, homodimer, heterodimer, RXR partner
   HRE core sequence AAAGGTCA (DR-5, half-site, NBRE, NuRE)
Partners NGFI-B (physical, functional): DNA binding4; NOR1 (physical, functional): DNA binding4; RXR (physical, functional): DNA binding5,6; P57KIP2 (physical, functional): inhibition of NURR1 transcriptional activity7; PIASγ (physical, functional): repression of NURR1 transcriptional activity8
Agonists Receptor lacks ligand-binding pocket9
Antagonists Receptor lacks ligand-binding pocket9
Coactivators
Corepressors
Biologically important isoforms NURR2 {Hs, Mm, Rn}: has a novel cryptic exon located upstream in the NURR1 promoter region and is generated by alternative splicing at exons 1, 2, and 6; lacks the C-terminal sequences corresponding to the ligand-binding domain or dimerization domain; inactive by itself, but may be able to inhibit transactivation by interaction with members of the NGFI-B family10
Tissue distribution Nervous system (mesencephalic dopaminergic neurons of the ventral tegmental area and of the substantia nigra), liver, pituitary, thymus, osteoblasts {Hs, Mm, Rn} [Northern blot, Q-PCR, in situ hybridization, Western blot, immunohistology]2,3,6,11–13
Functional assays
Main target genes Activated: osteopontin {Mm},14 osteocalcin {Rn},15 tyrosine hydroxylase {Mm},16 neuropilin {Mm}17
Mutant phenotype Homozygous knockout mice exhibit a complete loss of ventral mesencephalic dopaminergic neurons and altered gene expression in the dorsal motor nucleus of the brainstem; they have respiratory dysfunction and die at birth {Mm} [knockout]18–22
Human disease PD: in 8 of 107 individuals with familial PD, a T deletion was found at transcribed nucleotide position 291 upstream of the initiator AUG codon of NR4A2 and a T→G substitution at transcribed nucleotide position 245; these mutations did not affect the ORF but seem nevertheless dominant; later studies have not confirmed the importance of these mutations in PD23–25

  • aa, amino acids; chr., chromosome; HRE, hormone response element; Q-PCR, quantitative polymerase chain reaction; PD, Parkinson's disease; ORF, open reading frame

  • ↵1. Okabe T, Takayanagi R, Imasaki K, Haji M, Nawata H, and Watanabe T (1995) cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line. J Immunol 154: 3871-3879

  • ↵2. Scearce LM, Laz TM, Hazel TG, Lau LF, and 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

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

  • ↵4. Maira M, Martens C, Philips A, and Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19: 7549-7557

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

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

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

  • ↵8. Galleguillos D, Vecchiola A, Fuentealba JA, Ojeda V, Alvarez K, Gomez A, and Andres ME (2004) PIASγ represses the transcriptional activation induced by the nuclear receptor Nurr1. J Biol Chem 279: 2005-2011

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

  • ↵10. Ohkura N, Hosono T, Maruyama K, Tsukada T, and Yamaguchi K (1999) An isoform of Nurr1 functions as a negative inhibitor of the NGFI-B family signaling. Biochim Biophys Acta 1444: 69-79

  • ↵11. Bandoh S, Tsukada T, Maruyama K, Ohkura N, and Yamaguchi K (1997) Differential expression of NGFI-B and RNR-1 genes in various tissues and developing brain of the rat: comparative study by quantitative reverse transcription-polymerase chain reaction. J Neuroendocrinol 9: 3-8

  • ↵12. Mages HW, Rilke O, Bravo R, Senger G, and Kroczek RA (1994) NOT, a human immediate-early response gene closely related to the steroid/thyroid hormone receptor NAK1/TR3. Mol Endocrinol 8: 1583-1591

  • ↵13. Zetterstrom RH, Williams R, Perlmann T, and Olson L (1996) 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

  • ↵14. Lammi J, Huppunen J, and Aarnisalo P (2004) Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts. Mol Endocrinol 18: 1546-1557

  • ↵15. Pirih FQ, Tang A, Ozkurt IC, Nervina JM, and Tetradis S (2004) Nuclear orphan receptor Nurr1 directly transactivates the osteocalcin gene in osteoblasts. J Biol Chem 279: 53167-53174

  • ↵16. Sakurada K, Ohshima-Sakurada M, Palmer TD, and 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

  • ↵17. Hermanson E, Borgius L, Bergsland M, Joodmardi E, and Perlmann T (2006) Neuropilin1 is a direct downstream target of Nurr1 in the develooping brain stem. J Neurochem 97: 1403-1411

  • ↵18. Saucedo-Cardenas O, Quintana-Hau JD, Le WD, Smidt MP, Cox JJ, De Mayo F, Burbach JP, and 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

  • ↵19. Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, and Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science (Wash DC) 276: 248-250

  • ↵20. Castillo SO, Baffi JS, Palkovits M, Goldstein DS, Kopin IJ, Witta J, Magnuson MA, and 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

  • ↵21. Wallen AA, Castro DS, Zetterstrom RH, Karlen M, Olson L, Ericson J, and Perlmann T (2001) Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem. Mol Cell Neurosci 18: 649-663

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

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

  • ↵24. Ibanez P, Lohmann E, Pollak P, Durif F, Tranchant C, Agid Y, Durr A, and Brice A (2004) Absence of NR4A2 exon 1 mutations in 108 families with autosomal dominant Parkinson disease. Neurology 62: 2133-2134

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