Sanford-Burnham Medical Research Institute, Development and Aging Program, La Jolla, California, United States of America.
PLoS Biol. 2011 Apr;9(4):e1000609. doi: 10.1371/journal.pbio.1000609. Epub 2011 Apr 12.
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.
虽然视黄酸（RA）已被认为是调节前脑神经发生的外在信号，但 RA 信号调节的过程仍不清楚。在这里，对缺乏 RA 合成的视黄醛脱氢酶突变体小鼠胚胎的分析表明，基底神经节室下区 Raldh3 产生的 RA 对于 GABA 能分化是必需的，而脑膜中 Raldh2 产生的 RA 对于相邻皮质的发育是不必要的。从外侧神经节隆起（LGE）产生的神经球，其中 Raldh3 高度表达，产生内源性 RA，这对于分化为 GABA 能神经元是必需的。在 Raldh3⁻/⁻胚胎中，LGE 祖细胞不能分化为 GABA 能纹状体投射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 处理人胚胎干细胞的条件，这些条件导致 GABA 能中间神经元的高效分化，而不会出现 GABA 能纹状体投射神经元，从而为进一步研究提供了生成 GABA 能中间神经元的体外方法。我们的观察结果表明，内源性 RA 对于基底神经节中 LGE 衍生的 GABA 能神经元的产生是必需的，这确立了 RA 信号在大脑前脑发育中的关键作用。
