Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone
Role of retinoic acid during forebrain development begins late when Raldh3 generates retinoic acid in the ventral subventricular zone
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DOI：
10.1016/j.ydbio.2006.11.035
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发表时间：
2007-03-15
影响因子：
2.7
通讯作者：
Duester, Gregg
中科院分区：
文献类型：
--
作者：
Molotkova, Natalia;Molotkov, Andrei;Duester, Gregg
在鸡胚的额鼻表面外胚层中由Raldh 3合成的视黄酸（RA）已被建议通过调节Fgf 8、Shh和Meis 2表达在早期前脑图案形成中起作用。Raldh 3在E8.75小鼠胚胎中也有类似的表达，但Ra 1dh 2也在这个阶段的视泡中表达，这表明这两个基因可能在早期前脑模式中发挥作用。此外，Raldh 3在E12.5开始在前脑本身（外侧神经节隆起; LGE）中表达较晚，表明在前脑神经发生中的作用较晚。在这里，我们分析了小鼠胚胎携带单个或双无效突变的Ra 1dh 2和Raldh 3前脑发育的缺陷。Ral（-/-）; Raldh 3（-/-）胚胎在早期前脑中完全缺乏RA信号传导活性，但在前脑中表现出相对正常的Fgf 8、Shh和Meis 2表达。因此，我们发现没有明确的要求RA在控制这些重要的前脑模式化基因的表达，但Raldh 3在额鼻表面外胚层的表达被认为是需要正常的Fgf 8在嗅窝的表达。我们的研究表明，在腹侧前脑RA信号活动所需的LGE室管膜下区的Raldh 3的后期表达。重要的是，E18.5 Raldh 3（-/-）胚胎中多巴胺受体D2的表达在发育中的中脑核中基本上被消除，中脑核是靠近Raldh 3提供的RA来源的组织。我们的研究结果表明，RA在前脑发育过程中的作用开始晚时，Raldh 3表达在腹侧脑室下区启动。(c)2006年爱思唯尔公司All rights reserved.
Retinoic acid (RA) synthesized by Raldh3 in the frontonasal surface ectoderm of chick embryos has been suggested to function in early forebrain patterning by regulating Fgf8, Shh, and Meis2 expression. Similar expression of Raldh3 exists in E8.75 mouse embryos, but Ra1dh2 is also expressed in the optic vesicle at this stage suggesting that both genes may play a role in early forebrain patterning. Furthermore, Raldh3 is expressed later in the forebrain itself (lateral ganglionic eminence; LGE) starting at E12.5, suggesting a later role in forebrain neurogenesis. Here we have analyzed mouse embryos carrying single or double null mutations in Ra1dh2 and Raldh3 for defects in forebrain development. Raldh2(-/-);Raldh3(-/-) embryos completely lacked RA signaling activity in the early forebrain, but exhibited relatively normal expression of Fgf8, Shh, and Meis2 in the forebrain. Thus, we find no clear requirement for RA in controlling expression of these important forebrain patterning genes, but Raldh3 expression in the frontonasal surface ectoderm was found to be needed for normal Fgf8 expression in the olfactory pit. Our studies revealed that later expression of Raldh3 in the subventricular zone of the LGE is required for RA signaling activity in the ventral forebrain. Importantly, expression of dopamine receptor D2 in E18.5 Raldh3(-/-) embryos was essentially eliminated in the developing nucleus accumbens, a tissue lying close to the source of RA provided by Raldh3. Our results suggest that the role of RA during forebrain development begins late when Raldh3 expression initiates in the ventral subventricular zone. (c) 2006 Elsevier Inc. All rights reserved.