nuclear receptor subfamily 2, group E, member 1
|Classification||Mus musculus » Zinc-coordinating Group » Hormone-nuclear Receptor Family » Subfamily 2 (HNF4, RXR, TR2/4, DHR78, TLL, COUP-TF and EAR2, NR2A2/3, and 19 individual genes)|
|Related TF(s)||• NR2E1 • NR2E1 |
|Homologs ||(none defined here)|
|Links||ENSMUSG00000019803 (Ensembl) 21907 (Entrez Gene) Homologene |
|Synonyms||frc, fierce, XTLL, Tlx, TLL, Mtll, Mtl1|
The article completion score for this TF is 91%.
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Nr2e1 is a highly conserved 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. The DBD is connected to a C-terminal LBD by a hinge region.
Nr2e1 has been demonstrated to both repress and activate target genes. These functions are conferred upon numerous genes by binding to an AAGTCA consensus site within target promoters. By immunofluorescence Nr2e1 was shown to localize to the nucleus. 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. Expression of Nr2e1 is high during development of the mid- and forebrain and eye, and continues in neurogenic brain regions of the adult. Nr2e1 promotes proliferation of neural stem cells while repressing genes expressed during differentiation. Nr2e1 intricately controls the timing of proliferation within the developing cortex. A role in eye development, by controlling the proliferation of retinal progenitors, and expression in Müller glia has also been shown for Nr2e1.
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.
- 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)
- 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)
- Shi Y et al. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature, 427(6969):78-83. (PMID 14702088)
- 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)
- 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)
- 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)
- Elmi M et al. TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors. Molecular and cellular neurosciences (PMID 20599619)
- 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)
- 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)
- Yu RT et al. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature, 370(6488):375-9. (PMID 8047143)
- 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)
- Roy K et al. The Tlx gene regulates the timing of neurogenesis in the cortex. J. Neurosci., 24(38):8333-45. (PMID 15385616)
- 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)
- Zhang CL et al. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev., 20(10):1308-20. (PMID 16702404)
- 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)
- Denli AM et al. miR-9 and TLX: chasing tails in neural stem cells. Nat. Struct. Mol. Biol., 16(4):346-7. (PMID 19343066)
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)
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