Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells
Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells
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DOI：
10.1111/j.1432-0436.2006.00094.x
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发表时间：
2006-12-01
期刊：
影响因子：
2.9
通讯作者：
Dolle, Pascal
中科院分区：
文献类型：
--
作者：
Vermot, Julien;Messaddeq, Nadia;Dolle, Pascal
视黄酸 (RA) 是一种活性维生素 A 衍生物，是脊椎动物重要的发育信号分子。在这项研究中，我们评估了 RA 产生细胞的最小数量和/或特定分布是否可以支持正常的小鼠胚胎发育。视黄醛脱氢酶 2 (RALDH2) 是发育过程中发挥作用的主要 RA 合成酶。我们已经生成了 Raldh2 基因破坏的纯合胚胎干 (ES) 细胞系，并分析了具有野生型细胞各种贡献的嵌合胚胎。尽管胚胎几乎完全源自 Raldh2(-/-) 细胞，但其表型与相应的种系无效突变体相同，即使少量 (< 10%) 野生型细胞的存在也可以挽救大部分形态发生缺陷，包括胚胎转向和轴向伸长，以及心管的左右成环。在表型拯救的 Raldh2(-/-) 嵌合体中没有观察到野生型细胞分布的一致偏差。对 RA 敏感转基因的分析表明，RA 可以从野生型细胞中扩散出来，并在 Raldh2 缺陷细胞中引发广泛的转录反应。我们的结果表明，很少有野生型 RA 产生细胞，即使以明显的随机分布存在，也能支持小鼠胚胎的早期形态发生。然而，Raldh2(-/-)嵌合胎儿表现出肺异常、持续动脉干和异常心肌分化，表明随后的RA依赖性事件不能通过野生型细胞的嵌合存在来完全挽救。
Retinoic acid (RA), the active vitamin A derivative, is an important developmental signaling molecule in vertebrates. In this study, we have assessed whether minimal numbers and/or specific distributions of RA-producing cells can support normal mouse embryonic development. Retinaldehyde dehydrogenase 2 (RALDH2) is the main RA-synthesizing enzyme acting during development. We have generated an embryonic stem (ES) cell line homozygous for an Raldh2 gene disruption, and have analyzed chimeric embryos with various contributions of wild-type cells. Whereas embryos almost completely derived from Raldh2(-/-) cells phenocopy the corresponding germline null mutants, the presence of even small numbers (< 10%) of wildtype cells can rescue most of the morphogenetic defects, including embryonic turning and axial elongation, and left-right looping of the heart tube. No consistent bias in the distribution of wild-type cells was observed in the phenotypically rescued Raldh2(-/-) chimeras. Analysis of an RA-sensitive transgene indicates that RA can diffuse from wild-type cells and elicit a widespread transcriptional response in Raldh2-deficient cells. Our results show that few wild-type RA-producing cells, even when present in apparent random distributions, can support early morphogenesis of the mouse embryo. However, the Raldh2(-/-) chimeric fetuses display lung abnormalities, persistent truncus arteriosus, and abnormal myocardial differentiation, showing that subsequent RA-dependent events cannot be fully rescued by the mosaic presence of wild-type cells.