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
N1 - Funding Information:
Work in Karolinska was supported by Hjärnfonden, European Union (Strokemap and NeuroStemCell projects), Swedish Foundation for Strategic Research (SRL Program), Karolinska Institutet (Strategic Research Program and Thematic Center in Stem Cells and Regenerative Medicine) and the Swedish Research Council (DBRM, 2008:2811, 2011-3116 and 3318). The authors are grateful to L. Jansson-Sjöstrand and J. Söderlund for technical assistance, A. Nanni for secretarial help and S. Yang for help with artwork. Work in Swansea was supported by funding from the UK Research Councils Biotechnology and Biological Sciences Research Council (BB/C515771/2, BB/C511356/1 and BB/I001735/1 to W.J.G. and BB/H001018/1 to Y.W.). S.T. was supported by the Swedish Medical Research Council and the Onassis Foundation.
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 -