title: Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis.
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.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Theofilopoulos
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Satish Srinivas
authors.initials: SS
authors.lastname: Kitambi
authors.forename: Paola
authors.initials: P
authors.lastname: Sacchetti
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Sousa
authors.forename: Karl
authors.initials: K
authors.lastname: Bodin
authors.forename: Jayne
authors.initials: J
authors.lastname: Kirk
authors.forename: Carmen
authors.initials: C
authors.lastname: Saltó
authors.forename: Magnus
authors.initials: M
authors.lastname: Gustafsson
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Toledo
authors.forename: Kersti
authors.initials: K
authors.lastname: Karu
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
authors.forename: Jan
authors.initials: J
authors.lastname: Sjövall
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
mesh_terms: D000818:Animals; D001931:Brain Mapping / Q000379:methods; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology; D008024:Ligands; D000071518:Liver X Receptors; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D055495:Neurogenesis; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015027:Zebrafish
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D019826:Cholic Acid; D004298:Dopamine