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The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids

Kristine Griffett1, Gonzalo Bedia-Diaz1, Lamees Hegazy1

  • 1Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA.

Cell Chemical Biology
|August 9, 2020
PubMed

Insights

This study identifies retinoids as functional ligands for TLX, a nuclear receptor crucial for neurogenesis and glioblastomas. These findings reveal TLX as a potential therapeutic target for cognitive disorders and brain tumors.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Oncology

Background:

  • TLX (tailless homolog) is an orphan nuclear receptor vital for neurogenesis and glioblastoma development.
  • TLX primarily acts as a transcriptional repressor, but its natural or synthetic ligands were previously unknown.

Purpose of the Study:

  • To identify natural and synthetic retinoids that function as ligands for TLX.
  • To investigate the modulatory effects of these retinoids on TLX transcriptional activity.
  • To explore the therapeutic potential of targeting TLX.

Main Methods:

  • Screening of synthetic retinoids for TLX binding and activity modulation.
  • Identification of natural retinoids, including retinaldehyde, that bind to TLX.
  • Utilizing molecular dynamics simulations and mutational analysis to understand ligand-receptor interactions.

Main Results:

  • Identification of potent synthetic retinoids that bind to and modulate TLX activity (activation or inhibition).
  • Discovery of all-trans and 11-cis retinaldehyde as natural retinoids that bind and regulate TLX function.
  • Elucidation of the molecular basis for retinoid binding to TLX through computational and experimental approaches.

Conclusions:

  • Retinoids are functional ligands for the TLX nuclear receptor.
  • TLX activity can be modulated by specific natural and synthetic retinoids.
  • TLX represents a promising therapeutic target for cognitive disorders and glioblastomas.
Keywords:
cognitiondrug discoveryglioblastomaneurogenesisneurosciencenuclear receptorretinoidretinoid acidstem cell

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