Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis
Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis
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DOI：
10.1038/nchembio.1156
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发表时间：
2013-02-01
影响因子：
14.8
通讯作者：
Arenas, Ernest
中科院分区：
文献类型：
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作者：
Theofilopoulos, Spyridon;Wang, Yuqin;Arenas, Ernest
肝脏X受体（Lxr α和Lxr β）是体内腹侧中脑神经发生的关键配体依赖性核受体。然而，没有内源性中脑Lxr配体迄今已被确定。在这里，我们使用LC/MS和功能测定来鉴定胆酸作为新的Lxr配体。此外，24（S），25-环氧胆固醇（24，25-EC）被发现是发育中的小鼠中脑中最有效和最丰富的Lxr配体。两种Lxr配体均以Lxr依赖的方式促进斑马鱼体内神经发育。值得注意的是，每种配体选择性地调节不同中脑神经元群体的发育。而胆酸增加Brn 3a阳性红核神经元的存活和神经发生，24，25-EC促进多巴胺能神经发生。这些结果确定了一类全新的高度选择性和细胞类型特异性的神经发生和神经元存活调节因子。此外，24，25-EC促进胚胎干细胞的多巴胺能分化，表明Lxr配体因此可能有助于帕金森病的细胞替代和再生疗法的发展。
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.