Journal
NATURE CHEMICAL BIOLOGY
Volume 9, Issue 2, Pages 126-133Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1156
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Funding
- Hjarnfonden
- European Union
- Swedish Foundation for Strategic Research
- Karolinska Institutet
- Karolinska Institutet (Thematic Center in Stem Cells and Regenerative Medicine)
- Swedish Research Council (DBRM) [2008:2811, 2011-3116, 3318]
- UK Research Councils Biotechnology and Biological Sciences Research Council [BB/C515771/2, BB/C511356/1, BB/I001735/1, BB/H001018/1]
- Swedish Medical Research Council
- Onassis Foundation
- Biotechnology and Biological Sciences Research Council [BB/I001735/1, BB/C511356/1, BB/C515771/2, BB/H001018/1] Funding Source: researchfish
- BBSRC [BB/H001018/1, BB/I001735/1] Funding Source: UKRI
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Liver X receptors (Lxr alpha and Lxr beta) 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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