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NR2E1 is a highly conserved[1] human orphan nuclear receptor, consisting of a DNA-binding domain, hinge region, and ligand-binding domain. It is classified as an orphan as no ligand has yet been identified.

NR2E1 is important for brain development and its function has been shown to be conserved in Drosophila[2], Zebrafish[3], and mouse[4]. The mouse phenotype has been studied extensively and has proposed roles for NR2E1 in brain development, neural stem cells, and mental illness (see mouse Nr2e1 entry).

In humans, many different disorders including schizophrenia, socio- and psychopathy, and microcephaly have been investigated as having a potential underlying defect in NR2E1[5][6]. Recently, a study has found a genetic association between a single nucleotide polymorphism in human NR2E1 and Bipolar Disorder Type I[7]. Some studies have also indicated a role of NR2E1 in brain tumour formation, such as glioblastomas[8][9][10][11]. The closest homolog to NR2E1 is NR2E3 which has been demonstrated to cause Enhanced S-Cone Syndrome and implicated in some Retinitis Pigmentosa[12][13].

Molecularly, NR2E1 is described in the literature as mainly functioning by conferring strong repression upon target genes, including those expressed during differentiation of neural stem cells and regulators of cell cycle progression[14][15]. New targets have also been revealed recently upon which NR2E1 activates expression[16][17][18].

  1. Abrahams BS et al. Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci. Genomics, 80(1):45-53. (PMID 12079282)
  2. Pignoni F et al. The Drosophila gene tailless is expressed at the embryonic termini and is a member of the steroid receptor superfamily. Cell, 62(1):151-63. (PMID 2364433)
  3. Kitambi SS and Hauptmann G. The zebrafish orphan nuclear receptor genes nr2e1 and nr2e3 are expressed in developing eye and forebrain. Gene Expr. Patterns, 7(4):521-8. (PMID 17127102)
  4. Young KA et al. Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent. Behav. Brain Res., 132(2):145-58. (PMID 11997145)
  5. Kumar RA et al. Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations. Genes Brain Behav., 6(6):503-16. (PMID 17054721)
  6. Kumar RA et al. Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes. BMC Med. Genet., 8:48. (PMID 17655765)
  7. Kumar RA et al. Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing. Am. J. Med. Genet. B Neuropsychiatr. Genet., 147B(6):880-9. (PMID 18205168)
  8. Parsons DW et al. An integrated genomic analysis of human glioblastoma multiforme. Science, 321(5897):1807-12. (PMID 18772396)
  9. Sim FJ et al. Neurocytoma is a tumor of adult neuronal progenitor cells. J. Neurosci., 26(48):12544-55. (PMID 17135416)
  1. Phillips HS et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9(3):157-73. (PMID 16530701)
  2. Liu HK et al. The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation. Genes Dev., 24(7):683-95. (PMID 20360385)
  3. Haider NB et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat. Genet., 24(2):127-31. (PMID 10655056)
  4. Coppieters F et al. Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am. J. Hum. Genet., 81(1):147-57. (PMID 17564971)
  5. Shi Y et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature, 427(6969):78-83. (PMID 14702088)
  6. Sun G et al. Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc. Natl. Acad. Sci. U.S.A., 104(39):15282-7. (PMID 17873065)
  7. Iwahara N et al. Transcriptional activation of NAD+-dependent protein deacetylase SIRT1 by nuclear receptor TLX. Biochem. Biophys. Res. Commun., 386(4):671-5. (PMID 19555662)
  8. Qu Q et al. Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat. Cell Biol., 12(1):31-40; sup pp 1-9. (PMID 20010817)
  9. Elmi M et al. TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors. Molecular and cellular neurosciences (PMID 20599619)
FIGURE 1 Linkage disequilibrium map with six markers chosen for association analysis in bipolar disorder and schizophrenia
Genomic structure of NR2E1 and location of six markers selected for association analyses in bipolar disorder and schizophrenia.
A: Schematic of NR2E1 and closest neighboring gene SNX3.
B: Linkage disequilibrium (LD) map generated from the HAPMap data CEU population set. LD blocks (1, 2, and 3) were generated using the ‘‘Solid spine of LD’’ method. Markers that are tag SNPs are indicated in red. (Kumar et al. 2008)
This figure is from a publication by the authors of this article. Please click here to view the publication's entry in Pubmed (PMID 18205168).