Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia
Retinoic Acid Functions as a Key GABAergic Differentiation Signal in the Basal Ganglia
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DOI：
10.1371/journal.pbio.1000609
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发表时间：
2011-04-01
期刊：
影响因子：
9.8
通讯作者：
Duester, Gregg
中科院分区：
文献类型：
--
作者：
Chatzi, Christina;Brade, Thomas;Duester, Gregg
尽管视黄酸（RA）被认为是调节前脑神经发生的外部信号，但RA信号调节的过程尚不清楚。在此，对缺乏RA合成的视网膜脱氢酶突变型小鼠胚胎的分析表明，RALDH3在基底神经节的下脑室内区域中产生的RA是GABAergic分化所必需的，而RALDH2在脑膜中产生的RA是为了开发脑膜的RALDH2所产生的RA。由外侧神经节隆起（LGE）产生的神经球，高度表达RALDH3，产生内源性RA，这是分化与GABA能神经元所必需的。在raldh3（ - / - ）胚胎中，LGE祖细胞无法分化为GABA能纹状体投影神经元或迁移到嗅球和皮质的GABA能中间神经元。我们描述了RA治疗人类胚胎干细胞的条件，这些条件可有效地分化为GABA能中间神经元的异质种群，而无需出现GABA能纹状体投射神经元，从而为GABA能中间神经元提供了一种体外方法，以进行进一步研究。我们的观察到，基底神经节中产生LGE衍生的GABA能神经元所必需的内源性RA是RA信号在前脑发育中的关键作用。
Although retinoic acid (RA) has been implicated as an extrinsic signal regulating forebrain neurogenesis, the processes regulated by RA signaling remain unclear. Here, analysis of retinaldehyde dehydrogenase mutant mouse embryos lacking RA synthesis demonstrates that RA generated by Raldh3 in the subventricular zone of the basal ganglia is required for GABAergic differentiation, whereas RA generated by Raldh2 in the meninges is unnecessary for development of the adjacent cortex. Neurospheres generated from the lateral ganglionic eminence (LGE), where Raldh3 is highly expressed, produce endogenous RA, which is required for differentiation to GABAergic neurons. In Raldh3(-/-) embryos, LGE progenitors fail to differentiate into either GABAergic striatal projection neurons or GABAergic interneurons migrating to the olfactory bulb and cortex. We describe conditions for RA treatment of human embryonic stem cells that result in efficient differentiation to a heterogeneous population of GABAergic interneurons without the appearance of GABAergic striatal projection neurons, thus providing an in vitro method for generation of GABAergic interneurons for further study. Our observation that endogenous RA is required for generation of LGE-derived GABAergic neurons in the basal ganglia establishes a key role for RA signaling in development of the forebrain.