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For other uses, see TLX (disambiguation).

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.[5] TLX is a member of the nuclear receptor family of intracellular transcription factors.

TLX is part of the nuclear receptor subfamily 2 of retinoid X receptor-like proteins. However, unlike the retinoid X receptors, in typical physiologic circumstances it mostly binds to DNA by itself (as a monomer) instead of binding to another protein as a dimer. Using the type I-IV classification system, this means it’s likely a type IV nuclear receptor.[6]

Function

TLX regulates the expression of another nuclear receptor, RAR.[7][non-primary source needed]

TLX also is essential for normal brain-eye coordination and appears to play a role in control of aggressive behavior.[8]

Adult neural stem cells are nuclear receptor TLX-positive and TLX expression in these cells is crucial in maintaining their undifferentiated state.[9] 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.[10]

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.[11]

Ligands

TLX was previously an orphan receptor, a receptor without a known endogenous ligand.[6] However, it is now known that the fatty acid oleic acid as an endogenous agonist of TLX.[12][13][14] Oleic acid is peripherally selective, necessitating the use of synthetic drugs to act on this receptor for potential medical applications.[12]

Amdiglurax (NSI-189, ALTO-100) has been disclosed as a highly potent TLX agonist, with a reported EC50Tooltip half-maximal effective concentration of 36.1 pM (0.0361 nM) in an ALPHA assay.[15][16][17]

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.[18]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000112333 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019803 – Ensembl, May 2017
  3. ^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Jackson A, Panayiotidis P, Foroni L (May 1998). “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. doi:10.1006/geno.1998.5270. PMID 9628820.
  6. ^ a b Nelson AT, Wang Y, Nelson ER (November 2021). “TLJ, an orphan nuclear receptor with emerging roles in physiology and disease”. Endocrinology. 162 (11) bqab184. doi:10.1210/endocr/bqab184. PMC 8462384.
  7. ^ Kobayashi M, Yu RT, Yasuda K, Umesono K (December 2000). “Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX”. Molecular and Cellular Biology. 20 (23): 8731–8739. doi:10.1128/MCB.20.23.8731-8739.2000. PMC 86495. PMID 11073974.
  8. ^ Abrahams BS, Kwok MC, Trinh E, Budaghzadeh S, Hossain SM, Simpson EM (July 2005). “Pathological aggression in “fierce” mice corrected by human nuclear receptor 2E1″. The Journal of Neuroscience. 25 (27): 6263–6270. doi:10.1523/JNEUROSCI.4757-04.2005. PMC 6725287. PMID 16000615.
  9. ^ Shi Y, Chichung Lie D, Taupin P, Nakashima K, Ray J, Yu RT, et al. (January 2004). “Expression and function of orphan nuclear receptor TLX in adult neural stem cells”. Nature. 427 (6969): 78–83. Bibcode:2004Natur.427…78S. doi:10.1038/nature02211. PMID 14702088. S2CID 6495861.
  10. ^ Zhang CL, Zou Y, He W, Gage FH, Evans RM (February 2008). “A role for adult TLX-positive neural stem cells in learning and behaviour”. Nature. 451 (7181): 1004–1007. Bibcode:2008Natur.451.1004Z. doi:10.1038/nature06562. PMID 18235445. S2CID 14445703.
  11. ^ Liu HK, Belz T, Bock D, Takacs A, Wu H, Lichter P, et al. (September 2008). “The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone”. Genes & Development. 22 (18): 2473–2478. doi:10.1101/gad.479308. PMC 2546695. PMID 18794344.
  12. ^ a b McNerlin C, Guan F, Bronk L, Lei K, Grosshans D, Young DW, et al. (November 2022). “Targeting hippocampal neurogenesis to protect astronauts’ cognition and mood from decline due to space radiation effects”. Life Sciences in Space Research. 35. Amst: 170–179. Bibcode:2022LSSR…35..170M. doi:10.1016/j.lssr.2022.07.007. PMID 36336363. While TLX/NR2E1 has been a promising therapeutic target given its critical role in neural stem cell biology (Benod et al., 2014), its classification as an orphan nuclear receptor (with no known endogenous ligand) has hampered its utilization. However, Kandel and collaborators recently identified this long-sought endogenous ligand to be the mono-unsaturated fatty acid cis18:1ω9, oleic acid, thereby de-orphanizing this important receptor (Kandel et al., 2022). The discovery of the endogenous ligand made the TLX/NR2E1 (i.e. oleic acid receptor) a druggable target that could at the same time increase neurogenesis and alleviate neuroinflammation, both affected by radiation. However, while it would be the easiest to stimulate TLX/NR2E1 by its ligand, oleic acid, this is not possible as this fatty acid does not easily penetrate blood-brain-barrier.
  13. ^ Kandel P, Semerci F, Mishra R, Choi W, Bajic A, Baluya D, et al. (March 2022). “Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis”. Proceedings of the National Academy of Sciences of the United States of America. 119 (13) e2023784119. doi:10.1073/pnas.2023784119. PMC 9060471. PMID 35333654.
  14. ^ Shi Y, Evans RM, Gage FH (April 2022). “Oleic acid regulates hippocampal neurogenesis as a TLX ligand”. Proceedings of the National Academy of Sciences of the United States of America. 119 (15) e2203038119. doi:10.1073/pnas.2203038119. PMC 9169763. PMID 35344400.
  15. ^ Liu T. “BindingDB”. www.bindingdb.org.
  16. ^ PubChem. “PubChem-Bioassay”. PubChem.
  17. ^ WO application 2022140643, Young DU, Kandel PU, Semerci FU, Maletic-Savatic MU, Chamakuri SU, ”Small-molecule modulators of the orphan nuclear receptor TLX”, published 2022-06-30, assigned to Baylor College Medicine [US] and Semerci Fatih [US] 
  18. ^ Benod C, Villagomez R, Filgueira CS, Hwang PK, Leonard PG, Poncet-Montange G, et al. (2014). “The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable”. PLOS ONE. 9 (6) e99440. Bibcode:2014PLoSO…999440B. doi:10.1371/journal.pone.0099440. PMC 4060991. PMID 24936658.

Further reading