Disease relevance of Nr4a2

• These results suggest that putative Nurr1 ligands may be useful for treatment of Parkinson's disease and other disorders of midbrain dopamine circuitry [1].
• Decreased Nurr1 expression is found in the autopsied PD midbrains, particularly in neurons containing Lewy bodies, as well as in peripheral lymphocytes of patients with parkinsonian disorders [2].
• Furthermore, the central respiratory rhythm, generated from isolated brainstem-spinal cord preparations, exhibits impaired response to hypoxia in mice lacking Nurr1 [3].
• Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice [3].
• Dopamine (DA) levels may be regulated by Nurr1, and as DA is involved in both central and peripheral respiratory control, we hypothesized that lack of Nurr1 may impair breathing and cause death by respiratory failure [3].

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

• Dopamine neuron agenesis in Nurr1-deficient mice [1].
• Mice lacking Nurr1 failed to generate midbrain dopaminergic neurons, were hypoactive, and died soon after birth [1].
• Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells [6].
• These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen [6].
• We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells [7].

Chemical compound and disease context of Nr4a2

• Elevated locomotor activity without altered striatal dopamine contents in Nurr1 heterozygous mice after acute exposure to methamphetamine [8].
• IPX-750 was evaluated in the Parkinson's disease animal models, including MPTP mouse model, the 6-hydroxydopamine (6-OHDA) rat model and the Nurr1(+/-) knockout mouse model [9].

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

• The orphan nuclear receptor Nurr1 is essential for development of midbrain dopamine (DA) cells [11].
• 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 [12].
• In addition, our analyses establish Nurr1 as an early marker for the dorsal motor nucleus (DMN) of the vagus nerve [11].
• Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem [11].
• Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation [13].

Associations of Nr4a2 with chemical compounds

• Nurr1 (Nr4a2) is a transcription factor expressed in dopamine cells from early development and throughout life [14].
• To ascertain the function of an orphan nuclear receptor Nurr1, a transcription factor belonging to a large gene family that includes receptors for steroids, retinoids, and thyroid hormone, we generated Nurr1-null mice by homologous recombination [12].
• L-Dihydroxyphenylalanine treatments, whether given to the pregnant dams or to the newborns, failed to rescue the Nurr1-null mice [12].
• NGFI-B, Nurr1, and Nor1 are three closely related orphan members of the steroid/thyroid hormone receptor superfamily [15].
• However, whereas retinoic acid receptor can inhibit ligand-dependent RXR activation, NGFI-B and Nurr1 allow efficient RXR activation through DR5 elements and thus define a distinct pathway for vitamin A signaling [15].
• Nurr1 (+/-) male mice displayed a reduced dopamine turnover in the striatum and an enhanced dopamine turnover in the prefrontal cortex, while female mice showed an opposite pattern [16].

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].

References