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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

Nr2e1 is an orphan nuclear receptor and no ligand has yet been identified. Since it can bind and functionally repress a luciferase construct in HEK293 cells, which is an unrelated cell-type compared to endogenous expression, it may in fact be a constitutive nuclear receptor with no ligand. In the eye, atrophin-1 has been shown to be recruited as a co-repressor[1]. Additionally, in neural stem cells, Hdac3 and Hdac5 are shown to be recruited to confer repression upon target genes[2]. Deletion and mutation studies of an IXXLL amino acid motif indicated that this region was necessary for interactions with HDACs[2]. The repressive effects of Nr2e1 upon target genes were significantly relieved and neural stem cell proliferation decreased upon treatment of HDAC inhibitors, VPA and TSA, or HDAC siRNAs[2].

In neural stem cells (NSCs) co-IP has shown Nr2e1 to interact with LSD1[3]. Treatment with pargyline and tranylcypromine LSD1 inhibitors relieved repression of a p21-luciferase construct which was cotransfected with Nr2e1 and LSD1 in vitro, an effect also confirmed by siRNA experiments[3]. Similarly, co-IP demonstrated interaction between Sp1 and Nr2e1, and recruitment of PCAF by Nr2e1 at the Mash1-promoter[4].

Expression of soluble Wnt7a in HEK293 and co-cultured with NSCs demonstrated increased proliferation and self-renewal of the NSCs[5]. This effect was also demonstrated when Nr2e1 siRNA-treated cells decreased proliferation of wild-type NSCs and were rescued by Wnt7a-expressing HEK293 cells[5]. The active form of β-catenin ΔN90 given intracranially to Nr2e1-null mice rescued cell proliferation in the SVZ, further corroborating this interplay between the Wnt signalling pathway and Nr2e1[5].

Recently, it has been shown that Nr2e1 is regulated through a negative feedback loop by miRNA-9, and that Nr2e1 can bind downstream of the miRNA-9 gene[6][7]. An miR-9 binding site was identified in the 3' UTR of Nr2e1 mRNA and overexpression of miR-9 resulted in decreased proliferation and precocious differentiation; expression of a deletion construct lacking the 3' UTR reversed this effect[7]. This premature differentiation was also demonstrated in vivo by performing in utero electroporation[7]. Interestingly, anti-sense knock-down of miR-9 resulted in 1.37-fold increased proliferation as measured by BrdU incorporation[7].

Similarly, an interaction with microRNA let-7b was demonstrated, with a binding site in the 3' UTR of the Nr2e1 mRNA[8]. A luciferase reporter construct containing this 3' UTR segment demonstrated dose-dependent suppression by let-7b RNA duplexes in mouse neural stem cells. This was confirmed by RT-PCR and Western blot for Nr2e1, and abolished by mutating the binding site in the 3' UTR[8]. The expression of Nr2e1-target gene, Pten, was also demonstrated to be reduced after transfection of let-7b RNA duplexes[8].

In monkey fibroblast CV-1 cells, overexpression of NR2E1 (chick, mouse, or human) resulted in an enhanced all-trans retinoic acid-based induction of the RARβ2 promoter - this effect seems consistent with the high levels of expression of Nr2e1 in primary chick embryonic retinal cells[9].

Nr2e1 is known to bind the Pax2 promoter to confer repression - recently it was shown that this repression could be relieved in retinal astrocytes by application of both BMP7 and SHH together or individually, indicative of an additive effect, without having an effect on Nr2e1 protein levels[10]. Nr2e1 was shown to bind less to the promoter of Pax2 under these conditions by EMSAs and ChIP-qPCR[10]. This was accompanied by an increase of members of the BMP and SHH pathways, pSMAD1 and GLI2 at the Pax2 promoter, which co-immunoprecipitated with Nr2e1[10].

Genetically, the Pax6 small-eye (Sey) mutation significantly enhances the Nr2e1-null phenotype, resulting in enhanced dorsal shift of subpallial markers, both as Sey/+;Nr2e1-/- and even more so with Sey/Sey;Nr2e1-/-[11]. Other evidence for this genetic interaction comes from work in Xenopus where both Xtll and Xpax6 are expressed in the brain, eye and testes; the fusion of the DBD of Xtll to the engrailed repressor domain resulted in specific inhibition of eye vesicle evagination and a reduction in Xpax6 expression[12].

In Xenopus animal cap experiments, Noggin, Pax6, Six3 and Lhx2 were each shown to increase Xtll expression[13].

References
  1. Zhang CL et al. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev., 20(10):1308-20. (PMID 16702404)
  2. 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)
  3. Sun G et al. Histone demethylase LSD1 regulates neural stem cell proliferation. Mol. Cell. Biol., 30(8):1997-2005. (PMID 20123967)
  4. Elmi M et al. TLX activates MASH1 for induction of neuronal lineage commitment of adult hippocampal neuroprogenitors. Molecular and cellular neurosciences (PMID 20599619)
  5. 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)
  6. Denli AM et al. miR-9 and TLX: chasing tails in neural stem cells. Nat. Struct. Mol. Biol., 16(4):346-7. (PMID 19343066)
  7. Zhao C et al. A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat. Struct. Mol. Biol., 16(4):365-71. (PMID 19330006)
  1. Zhao C et al. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc. Natl. Acad. Sci. U.S.A., 107(5):1876-81. (PMID 20133835)
  2. Kobayashi M et al. Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX. Mol. Cell. Biol., 20(23):8731-9. (PMID 11073974)
  3. Sehgal R et al. BMP7 and SHH regulate Pax2 in mouse retinal astrocytes by relieving TLX repression. Dev. Biol. (PMID 19505455)
  4. Stenman J et al. Tlx and Pax6 co-operate genetically to establish the pallio-subpallial boundary in the embryonic mouse telencephalon. Development, 130(6):1113-22. (PMID 12571103)
  5. Hollemann T et al. The Xenopus homologue of the Drosophila gene tailless has a function in early eye development. Development, 125(13):2425-32. (PMID 9609825)
  6. Zuber ME et al. Specification of the vertebrate eye by a network of eye field transcription factors. Development, 130(21):5155-67. (PMID 12944429)
Ligands (author curated)
There are no data here... Yet.
Interactions (author curated)
  Interactor Experiment Types and Papers Nature of Interaction
1 Atn1 (mouse)
Two-hybrid
16702404
Not specified
2 Gli2 (mouse)
Co-purification
19505455
Not specified
3 Hdac3 (mouse)
Co-purification
17873065
Not specified
4 Hdac5 (mouse)
Co-purification
17873065
Not specified
5 Hdac7 (mouse)
Co-localization
17873065
Not specified
6 Kdm1 (mouse)
Co-purification
20123967
Not specified
7 Mir9-1 (mouse)
Not specified
19330006
Regulatory: decreases expression of this TF
8 Pax2 (mouse)
Not specified
10706625
Genetic
9 Pax6 (mouse)
Not specified
12571103
Genetic
10 Smad1 (mouse)
Co-purification
19505455
Not specified
11 Smad1 (mouse)
Co-purification
19505455
Not specified
12 Sp1 (mouse)
Co-purification
20599619
Not specified
Interactions (automatically populated)
There are no interaction data here... Yet.
Transcriptional regulators (automatically populated)
About this section
Data found in this section is cached from PAZAR, a public database of transcription factor and regulatory sequence annotation. Visit PAZAR at http://www.pazar.info/.
There are no data here... Yet.