Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis

Nat Chem Biol. 2013 Feb;9(2):126-33. doi: 10.1038/nchembio.1156. Epub 2012 Dec 23.


Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Mapping / methods
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Cholesterol / analogs & derivatives
  • Cholesterol / metabolism
  • Cholic Acid / metabolism
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Embryonic Stem Cells / cytology
  • Ligands
  • Liver X Receptors
  • Mesencephalon / metabolism*
  • Mice
  • Models, Biological
  • Neurogenesis*
  • Orphan Nuclear Receptors / metabolism*
  • Time Factors
  • Transfection
  • Zebrafish


  • Ligands
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • 24,25-epoxycholesterol
  • Cholesterol
  • Cholic Acid
  • Dopamine