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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
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Mus musculus
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Homo sapiens
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Transcription Factor Encyclopedia  BETA
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Overview

Nr2e1 is a highly conserved[1] orphan nuclear receptor also known as Tailless (or Tlx). The DNA-binding domain (DBD) at the N-terminal of Nr2e1 shares 100% identity with human NR2E1 and 81% similarity between Drosophila and humans. In the ligand-binding domain (LBD), mouse shares 99.6% similarity with humans, but less than 50% with Drosophila[2]. The DBD is connected to a C-terminal LBD by a hinge region.

Nr2e1 has been demonstrated to both repress[3][4] and activate target genes[5][6][7]. These functions are conferred upon numerous genes by binding to an AAGTCA consensus site within target promoters[8]. By immunofluorescence Nr2e1 was shown to localize to the nucleus[9][6]. Nr2e1 is currently an orphan nuclear receptor since no ligand has been identified, and it may act in a ligand-indepedent fashion due to its ability to act in unrelated cell-types (e.g. HEK293) in luciferase assays[4]. Expression of Nr2e1 is high during development of the mid- and forebrain and eye, and continues in neurogenic brain regions of the adult[10][11]. Nr2e1 promotes proliferation of neural stem cells while repressing genes expressed during differentiation. Nr2e1 intricately controls the timing of proliferation within the developing cortex[12][13]. A role in eye development, by controlling the proliferation of retinal progenitors, and expression in Müller glia has also been shown for Nr2e1[14][15].

Coregulators are commonly found for nuclear receptors, but few interactors have been identified thus far for Nr2e1 (see Interactions tab). However, interplay with miRNAs have been identified, as demonstrated by a negative feedback loop with miRNA-9 which fine-tunes the function of Nr2e1 in the cell[16].

References
  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. Jackson A et al. The human homologue of the Drosophila tailless gene (TLX): characterization and mapping to a region of common deletion in human lymphoid leukemia on chromosome 6q21. Genomics, 50(1):34-43. (PMID 9628820)
  3. Shi Y et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature, 427(6969):78-83. (PMID 14702088)
  4. 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)
  5. 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)
  6. 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)
  7. Elmi M et al. TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors. Molecular and cellular neurosciences (PMID 20599619)
  8. DeMeo SD et al. Specificity of DNA-binding by the FAX-1 and NHR-67 nuclear receptors of Caenorhabditis elegans is partially mediated via a subclass-specific P-box residue. BMC Mol. Biol., 9:2. (PMID 18179707)
  1. Li W et al. Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain. Mol. Endocrinol., 22(1):56-64. (PMID 17901127)
  2. Yu RT et al. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature, 370(6488):375-9. (PMID 8047143)
  3. Monaghan AP et al. The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. Development, 121(3):839-53. (PMID 7720587)
  4. Roy K et al. The Tlx gene regulates the timing of neurogenesis in the cortex. J. Neurosci., 24(38):8333-45. (PMID 15385616)
  5. Land PW and Monaghan AP. Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. Cereb. Cortex, 13(9):921-31. (PMID 12902391)
  6. Zhang CL et al. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev., 20(10):1308-20. (PMID 16702404)
  7. Miyawaki T et al. Tlx, an orphan nuclear receptor, regulates cell numbers and astrocyte development in the developing retina. J. Neurosci., 24(37):8124-34. (PMID 15371513)
  8. Denli AM et al. miR-9 and TLX: chasing tails in neural stem cells. Nat. Struct. Mol. Biol., 16(4):346-7. (PMID 19343066)
Figures
FIGURE 1 Neuroanatomical hypoplasia in "fierce" (Nr2e1-null) mice is ameliorated by the human transgene.
The gross morphology of the "fierce" brain was compared to that of a wild-type animal. "Fierce" possessed greatly hypoplastic forebrain regions including olfactory bulbs and increased exposure of the midbrain colliculi. A mouse carrying a human random-insertion PAC clone containing human NR2E1 shows normal morphology on a wild-type background and corrects the "fierce" defects in a rescue cross. (Abrahams et al. 2005)
This figure is from a publication by the authors of this article. Please click here to view the publication's entry in Pubmed (PMID 16000615).