TY - JOUR
T1 - Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis
AU - Theofilopoulos, Spyridon
AU - Wang, Yuqin
AU - Kitambi, Satish Srinivas
AU - Sacchetti, Paola
AU - Sousa, Kyle M.
AU - Bodin, Karl
AU - Kirk, Jayne
AU - Saltó, Carmen
AU - Gustafsson, Magnus
AU - Toledo, Enrique M.
AU - Karu, Kersti
AU - Gustafsson, Jan Åke
AU - Steffensen, Knut R.
AU - Ernfors, Patrik
AU - Sjövall, Jan
AU - Griffiths, William J.
AU - Arenas, Ernest
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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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U2 - 10.1038/nchembio.1156
DO - 10.1038/nchembio.1156
M3 - Article
C2 - 23292650
AN - SCOPUS:84872677234
VL - 9
SP - 126
EP - 133
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 2
ER -