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Gene Review

Nr4a2  -  nuclear receptor subfamily 4, group A,...

Mus musculus

Synonyms: HZF-3, NOT, NUR-related factor 1, Nuclear receptor subfamily 4 group A member 2, Nurr1, ...
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Disease relevance of Nr4a2


Psychiatry related information on Nr4a2

  • In contrast to the same-aged, wild-type mice, old Nurr1+/- mice (>15 months) had a significant decrease in both rotarod performance and locomotor activities, suggesting a motor impairment that is analogous to parkinsonian deficit [4].
  • These data show a deficient prefrontal NGFI-B and Nurr1 expression in schizophrenia and bipolar disorder [5].

High impact information on Nr4a2


Chemical compound and disease context of Nr4a2


Biological context of Nr4a2

  • Transfection of Nurr1 in osteoblastic cells increased OPN mRNA expression [10].
  • In conclusion, Nurr1 activates the OPN promoter directly in osteoblastic cells, suggesting a role for Nurr1 in the regulation of bone homeostasis [10].
  • In the search for Nurr1-regulated genes that might explain this developmental phenotype, we found that expression of the receptor tyrosine kinase Ret is deregulated in these cells of Nurr1-deficient embryos [11].
  • These findings provide evidence for a new mechanism of DA depletion in vivo and suggest a unique role for Nurr1 in fetal development and/or postnatal survival [12].
  • In addition, Nurr1 expression was required for maintenance of the DA phenotype and mediated up-regulation of the tyrosine kinase Ret and associated trophic factor GDNF-family receptors alpha 1, 2, and 4 [13].

Anatomical context of Nr4a2


Associations of Nr4a2 with chemical compounds


Physical interactions of Nr4a2

  • We demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons [17].

Regulatory relationships of Nr4a2

  • Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons [18].
  • The expression of Nurr1 mRNA was enhanced by PTN [19].
  • Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells [20].
  • PGC-1alpha enhanced Nurr1-induced transactivation of a consensus 3xNBRE-luciferase construct and the rat (-1050)Ocn promoter-luciferase construct from 3.7- to 9.6- and 10.1-fold, respectively [21].
  • Importantly, Nrp1 expression was down-regulated in this area in Nurr1 null mice [22].

Other interactions of Nr4a2

  • In conclusion, regulation of Ret by Nurr1 in midbrain DA neurons and in the DMN has implications for both embryonal development and adult physiology in which signaling by neurotrophic factors plays important roles [11].
  • Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1 [23].
  • Furthermore, they also expressed other midbrain DA markers, including Nurr1 and Pitx3, and released significant amounts of DA [24].
  • Together, these data suggest that Nurr1 may function to modify TH and GTPCH expression and dopamine synthesis [25].
  • Induction of Nurr1 at nestin-positive precursor and later stages of ES cell differentiation produced a non-neuronal DA cell type including functional DA transporters [13].

Analytical, diagnostic and therapeutic context of Nr4a2

  • To begin to understand the physiological implications of these functional differences we used in situ hybridization to compare the distribution of Nor1, NGFI-B, and Nurr1 messenger RNAs during different developmental stages [15].
  • In addition, specific gene analyses by RT-PCR demonstrated expression of an early central nerve system, mature neuron, and midbrain dopaminergic neuron-specific molecules (i.e., nestin, middle molecular mass neurofilament protein, Nurr1, and TH, respectively) [26].
  • Our results revealed that reduced Nurr1 expression, using Nurr1 siRNA in MC3T3-E1 cells, affected the expression of osteoblast differentiation marker genes, osteocalcin (OCN) and collagen type I alpha 1 (COL1A1), as measured by quantitative real-time PCR [27].
  • Therefore, fetal ventral mesencephalic tissue from embryonic day (E) 9.5-10.5 fetuses from Nurr1 mutant mice was co-cultured with lateral ganglionic eminence (LGE) from WT fetuses using the 'roller-drum' culture technique [28].
  • Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures [29].


  1. Dopamine neuron agenesis in Nurr1-deficient mice. Zetterström, R.H., Solomin, L., Jansson, L., Hoffer, B.J., Olson, L., Perlmann, T. Science (1997) [Pubmed]
  2. The role of Nurr1 in the development of dopaminergic neurons and Parkinson's disease. Jankovic, J., Chen, S., Le, W.D. Prog. Neurobiol. (2005) [Pubmed]
  3. Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice. Nsegbe, E., Wallén-Mackenzie, A., Dauger, S., Roux, J.C., Shvarev, Y., Lagercrantz, H., Perlmann, T., Herlenius, E. J. Physiol. (Lond.) (2004) [Pubmed]
  4. Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Jiang, C., Wan, X., He, Y., Pan, T., Jankovic, J., Le, W. Exp. Neurol. (2005) [Pubmed]
  5. Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders. Xing, G., Zhang, L., Russell, S., Post, R. Schizophr. Res. (2006) [Pubmed]
  6. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. Zhou, T., Cheng, J., Yang, P., Wang, Z., Liu, C., Su, X., Bluethmann, H., Mountz, J.D. J. Exp. Med. (1996) [Pubmed]
  7. Retinoic acid prevents experimental Cushing syndrome. Páez-Pereda, M., Kovalovsky, D., Hopfner, U., Theodoropoulou, M., Pagotto, U., Uhl, E., Losa, M., Stalla, J., Grübler, Y., Missale, C., Arzt, E., Stalla, G.K. J. Clin. Invest. (2001) [Pubmed]
  8. Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine. Bäckman, C., You, Z.B., Perlmann, T., Hoffer, B.J. Behav. Brain Res. (2003) [Pubmed]
  9. Dopaminergic properties and experimental anti-parkinsonian effects of IPX750 in rodent models of Parkinson disease. Jiang, C., Wan, X., Jankovic, J., Christian, S.T., Pristupa, Z.B., Niznik, H.B., Sundsmo, J.S., Le, W. Clinical neuropharmacology. (2004) [Pubmed]
  10. Regulation of the osteopontin gene by the orphan nuclear receptor NURR1 in osteoblasts. Lammi, J., Huppunen, J., Aarnisalo, P. Mol. Endocrinol. (2004) [Pubmed]
  11. Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem. Wallén A, A., Castro, D.S., Zetterström, R.H., Karlén, M., Olson, L., Ericson, J., Perlmann, T. Mol. Cell. Neurosci. (2001) [Pubmed]
  12. 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. Castillo, S.O., Baffi, J.S., Palkovits, M., Goldstein, D.S., Kopin, I.J., Witta, J., Magnuson, M.A., Nikodem, V.M. Mol. Cell. Neurosci. (1998) [Pubmed]
  13. Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation. Sonntag, K.C., Simantov, R., Kim, K.S., Isacson, O. Eur. J. Neurosci. (2004) [Pubmed]
  14. Decreased ethanol preference and wheel running in Nurr1-deficient mice. Werme, M., Hermanson, E., Carmine, A., Buervenich, S., Zetterström, R.H., Thorén, P., Ogren, S.O., Olson, L., Perlmann, T., Brené, S. Eur. J. Neurosci. (2003) [Pubmed]
  15. Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Zetterström, R.H., Solomin, L., Mitsiadis, T., Olson, L., Perlmann, T. Mol. Endocrinol. (1996) [Pubmed]
  16. Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Rojas, P., Joodmardi, E., Hong, Y., Perlmann, T., Ogren, S.O. Mol. Psychiatry (2007) [Pubmed]
  17. Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons. Jacobs, F.M., van der Linden, A.J., Wang, Y., von Oerthel, L., Sul, H.S., Burbach, J.P., Smidt, M.P. Development (2009) [Pubmed]
  18. Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a. Castelo-Branco, G., Wagner, J., Rodriguez, F.J., Kele, J., Sousa, K., Rawal, N., Pasolli, H.A., Fuchs, E., Kitajewski, J., Arenas, E. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  19. Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells. Jung, C.G., Hida, H., Nakahira, K., Ikenaka, K., Kim, H.J., Nishino, H. FASEB J. (2004) [Pubmed]
  20. Parathyroid hormone induces expression of the nuclear orphan receptor Nurr1 in bone cells. Tetradis, S., Bezouglaia, O., Tsingotjidou, A. Endocrinology (2001) [Pubmed]
  21. PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. Nervina, J.M., Magyar, C.E., Pirih, F.Q., Tetradis, S. Bone (2006) [Pubmed]
  22. Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem. Hermanson, E., Borgius, L., Bergsland, M., Joodmardi, E., Perlmann, T. J. Neurochem. (2006) [Pubmed]
  23. Parathyroid hormone induces the NR4A family of nuclear orphan receptors in vivo. Pirih, F.Q., Aghaloo, T.L., Bezouglaia, O., Nervina, J.M., Tetradis, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  24. Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro. Chung, S., Shin, B.S., Hwang, M., Lardaro, T., Kang, U.J., Isacson, O., Kim, K.S. Stem Cells (2006) [Pubmed]
  25. Reduced tyrosine hydroxylase and GTP cyclohydrolase mRNA expression, tyrosine hydroxylase activity, and associated neurochemical alterations in Nurr1-null heterozygous mice. Eells, J.B., Misler, J.A., Nikodem, V.M. Brain Res. Bull. (2006) [Pubmed]
  26. One-step induction of neurons from mouse embryonic stem cells in serum-free media containing vitamin B12 and heparin. Yamazoe, H., Kobori, M., Murakami, Y., Yano, K., Satoh, M., Mizuseki, K., Sasai, Y., Iwata, H. Cell transplantation. (2006) [Pubmed]
  27. Regulation of osteoblast differentiation by Nurr1 in MC3T3-E1 cell line and mouse calvarial osteoblasts. Lee, M.K., Choi, H., Gil, M., Nikodem, V.M. J. Cell. Biochem. (2006) [Pubmed]
  28. Generation of tyrosine hydroxylase-immunoreactive neurons in ventral mesencephalic tissue of Nurr1 deficient mice. Tornqvist, N., Hermanson, E., Perlmann, T., Stromberg, I. Brain Res. Dev. Brain Res. (2002) [Pubmed]
  29. Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Martinat, C., Bacci, J.J., Leete, T., Kim, J., Vanti, W.B., Newman, A.H., Cha, J.H., Gether, U., Wang, H., Abeliovich, A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
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