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FLASH GENE

Symbol

NR4A2

contributors: mct - updated : 16-01-2015

HGNC name	nuclear receptor subfamily 4, group A, member 2
HGNC id	7981

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PARK26 Parkinson disease 26
Location	2q24.1      Physical location : 157.180.945 - 157.189.287
Synonym name	nuclear receptor related 1
	neuron-derived orphan receptor-1
	orphan nuclear receptor NURR1
	transcriptionally inducible nuclear receptor related 1
	nur related protein-1, human homolog of
	NGFI-B/nur77 beta-type transcription factor homolog
	immediate-early response protein NOT
Synonym symbol(s)	NOT, TINUR, NURR1, RNR1, HZF-3, NOR-1, NURR77, NGFI-B

DNA

TYPE	functioning gene
STRUCTURE	8.34 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006186 8 initiation site 3546 NP_006177 - 598 - 2005 16243425

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain limbic system hippocampus   highly Homo sapiens   brain forebrain cerebral cortex frontal cortex highly Homo sapiens   nerve cranial nerve     highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous dopaminergic neuron Homo sapiens

cell lineage
cell lines	cell lines of T cell, B cell and fibroblasts
fluid/secretion

at STAGE

physiological period

embryo

Text	not confined to the developing midbrain, but is also detected in various embryonic brain regions along the neuroaxis

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal modulator domain
	AF1 domain
	short core activation region localized close to the N-terminus
	an AF2 domain
	a highly conserved zing finger DNA binding domain and a less conserved putative C terminal ligand domain
	a central bipartite (class II) zinc finger DNA binding domain

mono polymer

heteromer , dimer

HOMOLOGY

interspecies

homolog to murine Nr4a2

Homologene

FAMILY	NR4A subfamily of the nuclear receptor superfamily
	steroid/thyroid receptor superfamily

CATEGORY

receptor nuclear

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
text	translocates to the nucleus in response to EGF-stimulation of certain cell types

basic FUNCTION	may be functioning as a general coactivator of gene transcription with ligand-independent regulation
	playing an essential role in the development of midbrain dopamine cells and in the regulation of RET
	implicated in the development of dopaminergic cells of the ventral tegmental area (VTA) and the substantia nigra (SN)
	involved in the establishment and maintenance of the dopaminergic phenotype within specific central nervous system neuronal subpopulations including the nigrostriatal dopamine system
	may also play a role in the pathogenesis of Parkinson disease
	having a protective function in cartilage homeostasis by selectively repressing MMP gene expression during inflammation
	plays a pivotal role for mediating cytokine production from pathogenic T cells
	not only essential in the development of mensencephalic dopaminergic neurons and maintenance of their functions, but it may also play a role in the pathogenesis of Parkinson disease
	enhances 3,5-cyclic adenosine 5prime-monophosphate-dependent UCP1 gene transcription
	transcription factor essential for the development, survival, and functional maintenance of midbrain dopaminergic (DAergic) neurons
	playing a role in neuronal/astrocytic differentiation of neural precursor
	activating FABP5
	can enhance RA-induced signaling of PPARbeta/delta and DHA-induced activation of RXR, via the up-regulation of FABP5
	essential mediator of neuroprotection after exposure to neuropathological stress
	key downstream mediator of CREB1-induced neuroprotection
	NR4A1, NR4A2 modulate mesenchymal stromal cell migration
	induction of NR4A1, NR4A2, NR4A3 in activated mast cells and NR4A family nuclear receptors are implicated in the regulation of mast cell function
	NR4A2, NR4A1 functions directly at DNA repair sites by a process that requires phosphorylation by PRKDC, and represent an entirely novel component of DNA damage response in the process of DSB repair
	EGF-stimulation of cells may be a mechanism for the priming of cells for the actions of NR4A2 through increased stability
	NR4A2 and BDNF show a similar expression pattern during postnatal cerebellar development
	essential for the nigral dopaminergic neuron phenotype and function maintenance
	is necessary for both long-term memory for object location and object recognition
	NR4A1 and NR4A2 differentially contribute to object location versus object recognition memory
	NR4A1, NR4A2, NR4A3 have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis
	functions mainly in transcriptional activation to regulate a battery of genes expressed in dopaminergic neurons
	regulates key genes, including a battery of nuclear-encoded mitochondrial genes
	selectively contributes to the maintenance of normal expression levels of nuclear-encoded genes involved in oxidative respiration, but not of any other functional categories of nuclear-encoded mitochondrial genes
	is an orphan nuclear receptor best known for its essential role in the development and maintenance of midbrain dopaminergic (DA) neurons
	key midbrain dopamine (mDA) regulators (NR4A2, PITX3, and LMX1A) play overlapping as well as distinct roles during neurogenesis and neurotransmitter phenotype determination of mDA neurons
	NR4A1, NR4A2, NR4A3 are regulated by different physiological and pathophysiological settings known to be associated with marked alterations in glucose metabolism and energy status
	plays a key role in embryonic development and maintenance of mesencephalic dopaminergic neurons in the substantia nigra

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

heterodimerizing with retinoic X receptor (RXR)

INTERACTION

DNA	binding to FABP5 promoter

RNA

small molecule

protein	key regulators of CYP11B2 expression and of adrenal aldosterone production
	cooperating with PITX3 to promote terminal maturation of the midbrain dopamine neuron phenotype in embryonic stem cell cultures
	association between NR4A2 overexpression and upregulation of CDKN2C, suggesting a mechanism by which NR4A2 could regulate haematopoietic stem cells quiescence
	NR4A1, NR4A2 interact with PRKDC and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of PARP1
	potential molecular target of MIR-132 (MIR-132 could directly regulate the expression of NR4A2)
	is a downstream target of CREB1 and it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons
	NR4A2-TOP2B interaction may shed light on the pathologic role of NR4A2 defect in the nigro-striatal pathway deficiency associated with Parkinson disease
	PIN1 is a novel binding partner of NR4A1, NR4A2, NR4A3
	in melanoma cells both CRH and UCN1 regulate TYRP1 gene expression via NR4A2/NR4A1 production, independent of pro-opiomelanocortin or alpha-melanocyte-stimulating hormone stimulation
	NR4A2 represses TH expression via SIRT1 in human neural stem cells
	FOXA2 acts as a co-activator potentiating expression of the NR4A2-induced dopamine (DA) phenotype via epigenetic regulation
	PTH activates the orphan nuclear receptor NR4A2 to induce FGF23 transcription
	NR4A2 is an orphan transcription factor that influences the expression of several key proteins of dopaminergic (DA) neurons, including tyrosine hydroxylase (TH), dopamine transporter (SLC6A3), and vesicular monoamine transporter (SLC18A1)

cell & other

REGULATION

induced by	the cAMP axis in response to glucagon
		CREB1 in neurons exposed to stressful insults and function as mediator of CREB1-induced neuronal survival

Other	direct regulation by CREB1 after NMDAR stimulation
	degraded by the proteasome

ASSOCIATED DISORDERS

corresponding disease(s)

PARK26

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in familial Parkinson disease constitutional     --over   in cartilage derived from patients with osteoarthritis constitutional     --over   in the T cells isolated from the CNS of multiple sclerosis constitutional     --low   in end-stage dilated cardiomyopathy constitutional     --low   in patients with Parkinson disease

Susceptibility

to attention deficit hyperactivity disorder (ADHD) to Parkinson disease to autism spectrum disorder (ASD)

Variant & Polymorphism other	polymorphisms associated to attention deficit hyperactivity disorder (ADHD)
	copy-number variants (CNVs) in NR4A2 contribute significantly to autism spectrum disorder (ASD) risk

Candidate gene
Marker
Therapy target	molecular target for blocking inflammation and tissue destruction associated with chronic inflammatory diseases
	essential transcription factor for triggering the inflammatory cascade of multiple sclerosis and may serve as a therapeutic target

ANIMAL & CELL MODELS

	expression increased in diabetic mice that exhibit elevated gluconeogenesis
	Nurr1 ablation in mice recapitulates early features of Parkinson disease