Alternative titles; symbols
HGNC Approved Gene Symbol: NR2E1
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:108,166,022-108,188,809 (from NCBI)
By searching for genes located within the 6q21-q23 region of minimal deletion (RMD) associated with hematologic malignancies, Jackson et al. (1998) identified the human TLX homolog, also called NR2E1. By a combination of direct sequencing, exon trapping, and library screening, they isolated human TLX cDNAs. The predicted 386-amino acid human protein shares 97% and 99% identity with chick and mouse TLX, respectively. The highest degree of similarity between TLX and Drosophila tll is within the DBDs and the ligand-binding domains (LBDs) of the proteins. Northern blot analysis revealed that the approximately 3.9-kb TLX mRNA is expressed exclusively in brain.
Jackson et al. (1998) determined that the NR2E1 gene comprises 9 exons and spans 24 kb.
By genomic sequence analysis, Jackson et al. (1998) mapped the NR2E1 gene to chromosome 6q21-q23.
The product of the Drosophila terminal/gap gene 'tailless' (tll) is expressed in the embryonic brain and is required for brain development in flies. The tll protein is a ligand-activated nuclear receptor-type transcription factor. In 2 discrete subregions of the DNA-binding domain (DBD) that modulate the mode of DNA binding, the tll protein contains changes that distinguish it from all other nuclear receptors. Yu et al. (1994) identified the chick and mouse Tlx genes, encoding the vertebrate tll homolog. The vertebrate Tlx proteins are highly conserved, and both avian and mammalian Tlx contain the distinct tll DBD sequences. In vitro DNA-binding assays demonstrated that Tlx and tll share a target gene specificity that is unique among the nuclear receptor superfamily. Ectopic expression of chick Tlx in fly embryos caused a repression of segmentation comparable to that elicited by tll. In situ hybridization to chick and mouse embryos revealed that Tlx is expressed in the head ectoderm in early embryos. At later stages, cells expressing Tlx are localized in the ventricular zone of the neuroepithelial layer, suggesting that Tlx is involved in transcriptional control in undifferentiated neuroepithelial cells in the anterior regions of the developing vertebrate brain.
Shi et al. (2004) demonstrated that TLX maintains adult neural stem cells in an undifferentiated proliferative state. Shi et al. (2004) showed that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew, and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains failed to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescued their ability to proliferate and to self-renew. In vivo, TLX mutant mice showed a loss of cell proliferation and reduced labeling of nestin (600915) in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.
Sun et al. (2007) showed that Tlx interacted with a set of HDACs (e.g., HDAC3; 605166) in mouse neural stem cells and recruited these HDACs to Tlx target genes to repress their expression. Chemical inhibition of HDAC activity, knockdown of HDAC expression with small interfering RNA, or disruption of Tlx-HDAC interaction resulted in induction of the Tlx target genes p21 (CDKN1A; 116899) and Pten (601728) and marked inhibition of neural stem cell proliferation.
Using genetic approaches in mice, Zhang et al. (2008) demonstrated that TLX regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in a cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination resulted in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis did not affect contextual fear conditioning, locomotion, or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.
Liu et al. (2008) found that Tlx-positive cells of the subventricular zone of adult mouse brain were self-renewing stem cells. Inducible mutation of the Tlx gene in adult mouse brain led to complete loss of neurogenesis in the subventricular zone. Further studies showed that Tlx was required for transition from radial glial cells to astrocyte-like neural stem cells.
Monaghan et al. (1997) generated mutant mice lacking a functional Tlx protein. Homozygous mutant mice were viable at birth, indicating that Tlx is not required for prenatal survival. However, adult mutant mice showed a reduction in the size of rhinencephalic and limbic structures of the brain, including the olfactory, infrarhinal and entorhinal cortex, amygdala, and dentate gyrus. Both male and female mutant mice were more aggressive than usual, and females lacked normal maternal instincts. The authors considered the Tlx behavioral phenotype to be a massive disinhibition syndrome caused by missing or misrouted subcortical or limbic afferents to the hypothalamus or olfactory structures. They concluded that Tlx is required for the maintenance of the ventricular zone after stage E15, and that the disruption of the Tlx locus leads to impaired development of a specific subset of forebrain-derived structures.
Uemura et al. (2006) demonstrated that in the postnatal mouse retina, Tlx is strongly expressed in proangiogenic astrocytes, which secrete VEGF (192240) and fibronectin (135600). Tlx expression by retinal astrocytes was controlled by oxygen concentration and rapidly downregulated upon contact with blood vessels. In Tlx -/- mice, retinal astrocytes maintained VEGF expression, but the extracellular assembly of fibronectin matrices by astrocytes was severely impaired, leading to defective scaffold formation and a complete failure of normal retinal vascular development. Uemura et al. (2006) concluded that TLX is an essential component of the molecular network involved in the hypoxia-inducible proangiogenic switch in retinal astrocytes.
By immunostaining Tlx -/- and wildtype mouse neural retinas, Zhang et al. (2006) found that Tlx -/- mice had retinal 'voids' preceded by zones of outer segment thinning at earlier developmental stages. Tlx -/- mice showed enhanced generation of S-cones and developed severe early-onset retinal dystrophy. Using biochemical approaches, Zhang et al. (2006) showed that Tlx modulated retinal progenitor cell differentiation and cell cycle reentry by regulating expression of Pten and its target, cyclin D1 (CCND1; 168461). Tlx fine-tuned the progenitor differentiation program through phospholipase C (see 600220) and MAPK (see 176948) pathways and expression of cell type-specific transcriptional regulators. Tlx also interacted with atrophin-1 (DRPLA; 607462), a corepressor essential for development of multiple tissues.
Using a knockin mouse model, Schmouth et al. (2012) found that expression of a single copy of a BAC carrying human NR2E1 completely corrected abnormal retinal histology and electroretinograms in Nr2e1 -/- mice. However, NR2E1 did not fully correct defects in cerebrum and olfactory bulb hypoplasia in Nr2e1 -/- mice.
Jackson, A., Panayiotidis, P., Foroni, L. 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: 34-43, 1998. [PubMed: 9628820] [Full Text: https://doi.org/10.1006/geno.1998.5270]
Liu, H.-K., Belz, T., Bock, D., Takacs, A., Wu, H., Lichter, P., Chai, M., Schutz, G. The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone. Genes Dev. 22: 2473-2478, 2008. [PubMed: 18794344] [Full Text: https://doi.org/10.1101/gad.479308]
Monaghan, A. P., Bock, D., Gass, P., Schwager, A., Wolfer, D. P., Lipp, H.-P., Schutz, G. Defective limbic system in mice lacking the tailless gene. Nature 390: 515-517, 1997. [PubMed: 9394001] [Full Text: https://doi.org/10.1038/37364]
Schmouth, J.-F., Banks, K. G., Mathelier, A., Gregory-Evans, C. Y., Castellarin, M., Holt, R. A., Gregory-Evans, K., Wasserman, W. W., Simpson, E. M. Retina restored and brain abnormalities ameliorated by single-copy knock-in of human NR2E1 in null mice. Molec. Cell. Biol. 32: 1296-1311, 2012. [PubMed: 22290436] [Full Text: https://doi.org/10.1128/MCB.06016-11]
Shi, Y., Chichung Lie, D., Taupin, P., Nakashima, K., Ray, J., Yu, R. T., Gage, F. H., Evans, R. M. Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427: 78-83, 2004. [PubMed: 14702088] [Full Text: https://doi.org/10.1038/nature02211]
Sun, G., Yu, R. T., Evans, R. M., Shi, Y. Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation. Proc. Nat. Acad. Sci. 104: 15282-15287, 2007. [PubMed: 17873065] [Full Text: https://doi.org/10.1073/pnas.0704089104]
Uemura, A., Kusuhara, S., Wiegand, S. J., Yu, R. T., Nishikawa, S.-I. Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes. J. Clin. Invest. 116: 369-377, 2006. [PubMed: 16424942] [Full Text: https://doi.org/10.1172/JCI25964]
Yu, R. T., McKeown, M., Evans, R. M., Umesono, K. Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx. Nature 370: 375-379, 1994. [PubMed: 8047143] [Full Text: https://doi.org/10.1038/370375a0]
Zhang, C.-L., Zou, Y., Gage, F. H., Evans, R. M. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 20: 1308-1320, 2006. [PubMed: 16702404] [Full Text: https://doi.org/10.1101/gad.1413606]
Zhang, C.-L., Zou, Y., He, W., Gage, F. H., Evans, R. M. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451: 1004-1007, 2008. [PubMed: 18235445] [Full Text: https://doi.org/10.1038/nature06562]