Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis - PubMed (original) (raw)

doi: 10.1038/nchembio.1156. Epub 2012 Dec 23.

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

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Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis

Spyridon Theofilopoulos et al. Nat Chem Biol. 2013 Feb.

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.

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