TLX explained

Nuclear receptor TLX (homologue of the Drosophila tailless gene) also known as NR2E1 (Nuclear receptor subfamily 2 group E member 1) is a protein that in humans is encoded by the NR2E1 gene.^[1] TLX is a member of the nuclear receptor family of intracellular transcription factors.

Function

TLX regulates the expression of another nuclear receptor, RAR.^[2]

TLX also is essential for normal brain-eye coordination and appears to play a role in control of aggressive behavior.^[3]

Adult neural stem cells are nuclear receptor TLX-positive and TLX expression in these cells is crucial in maintaining their undifferentiated state.^[4] Furthermore, TLX regulates adult neural stem cell proliferation. Removal of TLX from the adult mouse brain resulted in a reduction of stem cell proliferation and spatial learning.^[5]

Tlx-positive cells of the subventricular zone of adult mouse brain are self-renewing stem cells. Mutation of the Tlx gene in adult mouse brain leads to complete loss of neurogenesis in the subventricular zone. Tlx is also required for transition from radial glial cells to astrocyte-like neural stem cells.^[6]

Ligands

TLX belongs to a small family of NRs that lack two helices in the ligand-binding domain, forming an enlarged binding pocket. Three compounds, termed ccrp1 - 3 (famprofazone, 1-(1,5-dimethylpyrazole-3-carbonyl)-4-(diphenylmethyl)piperazine, dydrogesterone), have been discovered in high-throughput screening that enhance TLX's ability of transcription repression with high potency.^[7]

Further reading

• Yu RT, McKeown M, Evans RM, Umesono K . Relationship between Drosophila gap gene tailless and a vertebrate nuclear receptor Tlx . Nature . 370 . 6488 . 375–9 . August 1994 . 8047143 . 10.1038/370375a0 . 1994Natur.370..375Y . 4326071 .
• Kobayashi M, Yu RT, Yasuda K, Umesono K . Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX . Molecular and Cellular Biology . 20 . 23 . 8731–9 . December 2000 . 11073974 . 86495 . 10.1128/MCB.20.23.8731-8739.2000 .
• Abrahams BS, Mak GM, Berry ML, Palmquist DL, Saionz JR, Tay A, Tan YH, Brenner S, Simpson EM, Venkatesh B . 6 . Novel vertebrate genes and putative regulatory elements identified at kidney disease and NR2E1/fierce loci . Genomics . 80 . 1 . 45–53 . July 2002 . 12079282 . 10.1006/geno.2002.6795 .
• Abrahams BS, Kwok MC, Trinh E, Budaghzadeh S, Hossain SM, Simpson EM . Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1 . The Journal of Neuroscience . 25 . 27 . 6263–70 . July 2005 . 16000615 . 10.1523/JNEUROSCI.4757-04.2005 . 6725287 .
• Kumar RA, Leach S, Bonaguro R, Chen J, Yokom DW, Abrahams BS, Seaver L, Schwartz CE, Dobyns W, Brooks-Wilson A, Simpson EM . 6 . Mutation and evolutionary analyses identify NR2E1-candidate-regulatory mutations in humans with severe cortical malformations . Genes, Brain and Behavior . 6 . 6 . 503–16 . August 2007 . 17054721 . 2040186 . 10.1111/j.1601-183X.2006.00277.x .
• Kumar RA, Everman DB, Morgan CT, Slavotinek A, Schwartz CE, Simpson EM . Absence of mutations in NR2E1 and SNX3 in five patients with MMEP (microcephaly, microphthalmia, ectrodactyly, and prognathism) and related phenotypes . BMC Medical Genetics . 8 . 48 . July 2007 . 17655765 . 1950490 . 10.1186/1471-2350-8-48 . free .
• Sun G, Yu RT, Evans RM, Shi Y . Orphan nuclear receptor TLX recruits histone deacetylases to repress transcription and regulate neural stem cell proliferation . Proceedings of the National Academy of Sciences of the United States of America . 104 . 39 . 15282–7 . September 2007 . 17873065 . 2000559 . 10.1073/pnas.0704089104 . 2007PNAS..10415282S . free .

Notes and References

1. 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 . 1 . 34–43 . May 1998 . 9628820 . 10.1006/geno.1998.5270 .
2. Kobayashi M, Yu RT, Yasuda K, Umesono K . Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX . Molecular and Cellular Biology . 20 . 23 . 8731–9 . December 2000 . 11073974 . 86495 . 10.1128/MCB.20.23.8731-8739.2000 .
3. Abrahams BS, Kwok MC, Trinh E, Budaghzadeh S, Hossain SM, Simpson EM . Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1 . The Journal of Neuroscience . 25 . 27 . 6263–70 . July 2005 . 16000615 . 10.1523/JNEUROSCI.4757-04.2005 . 6725287 .
4. Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT, Gage FH, Evans RM . 6 . Expression and function of orphan nuclear receptor TLX in adult neural stem cells . Nature . 427 . 6969 . 78–83 . January 2004 . 14702088 . 10.1038/nature02211 . 2004Natur.427...78S . 6495861 .
5. Zhang CL, Zou Y, He W, Gage FH, Evans RM . A role for adult TLX-positive neural stem cells in learning and behaviour . Nature . 451 . 7181 . 1004–7 . February 2008 . 18235445 . 10.1038/nature06562 . 2008Natur.451.1004Z . 14445703 .
6. Liu HK, Belz T, Bock D, Takacs A, Wu H, Lichter P, Chai M, Schütz G . 6 . The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone . Genes & Development . 22 . 18 . 2473–8 . September 2008 . 18794344 . 2546695 . 10.1101/gad.479308 .
7. Benod C, Villagomez R, Filgueira CS, Hwang PK, Leonard PG, Poncet-Montange G, Rajagopalan S, Fletterick RJ, Gustafsson JÅ, Webb P . 6 . The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable . PLOS ONE . 9 . 6 . e99440 . 2014 . 24936658 . 4060991 . 10.1371/journal.pone.0099440 . free . 2014PLoSO...999440B .