Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis

Spyridon Theofilopoulos, Yuqin Wang, Satish Srinivas Kitambi, Paola Sacchetti, Kyle M. Sousa, Karl Bodin, Jayne Kirk, Carmen Saltó, Magnus Gustafsson, Enrique M. Toledo, Kersti Karu, Jan Åke Gustafsson, Knut R. Steffensen, Patrik Ernfors, Jan Sjövall, William J. Griffiths, Ernest Arenas

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)126-133
Number of pages8
JournalNature Chemical Biology
Volume9
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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