Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis
- Authors
- Theofilopoulos, S., Wang, Y., Kitambi, S.S., Sacchetti, P., Sousa, K.M., Bodin, K., Kirk, J., Saltó, C., Gustafsson, M., Toledo, E.M., Karu, K., Gustafsson, J.A., Steffensen, K.R., Ernfors, P., Sjövall, J., Griffiths, W.J., and Arenas, E.
- ID
- ZDB-PUB-130110-27
- Date
- 2013
- Source
- Nature Chemical Biology 9(2): 126-133 (Journal)
- Registered Authors
- Kitambi, Satish Srinivas
- Keywords
- none
- 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
- Mesencephalon/metabolism*
- Mice
- Models, Biological
- Neurogenesis*
- Orphan Nuclear Receptors/metabolism*
- Time Factors
- Transfection
- Zebrafish
- PubMed
- 23292650 Full text @ Nat. Chem. Biol.
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.