Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives
Retinoic acid regulates morphogenesis and patterning of posterior foregut derivatives
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DOI：
10.1016/j.ydbio.2006.05.019
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发表时间：
2006-09-15
影响因子：
2.7
通讯作者：
Niederreither, Karen
中科院分区：
文献类型：
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作者：
Wang, Zengxin;Dolle, Pascal;Niederreither, Karen
维甲酸(RA)是一种胚胎信号分子，调节广泛的靶基因，因此是各种器官模式和分化的主要调节者。在这里，我们发现缺乏RA合成酶视黄醛脱氢酶2(RALDH2)的小鼠胚胎，如果在e7.5到e8.5之间通过补充母体RA从早期死亡中拯救出来，前肠区域缺乏活跃的RA信号。由此产生的突变体完全不能发育肺部。更多的前肠后衍生物(胃和十二指肠)的发育以及肝脏的生长也受到严重影响。在RA缺陷的胚胎中指定了一个初级肺芽，由于FGF10信号的缺陷和上皮中缺少激活的成纤维细胞生长因子靶基因，如Pea3和Bmp4，这些原始肺芽无法生长。特异的HOX和Tbx基因可能介导了这些RA的调节作用。通过延长RA补充剂至少到E10.5，突变体可以部分恢复前肠衍生物的发育，但肺生长和分支仍然有缺陷，发育不良的肺仅在右侧发育。这种情况很难恢复肺芽中的FGF10信号。RALDH2缺陷的前肠外植体培养显示出在RA或FGF10存在的情况下经历肺萌发和早期分支的能力。我们的数据表明，RA是HOX、Tbx和FGF10信号上游的早期胚胎肺和胃区基因表达的调节因子。(C)2006 Elsevier Inc.保留所有权利。
Retinoic acid (RA) is an embryonic signaling molecule regulating a wide array of target genes, thereby being a master regulator of patterning and differentiation in a variety of organs. Here we show that mouse embryos deficient for the RA-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2), if rescued from early lethality by maternal RA supplementation between E7.5 and E8.5, lack active RA signaling in the foregut region. The resulting mutants completely fail to develop lungs. Development of more posterior foregut derivatives (stomach and duodenum), as well as liver growth, is also severely affected. A primary lung bud is specified in the RA-deficient embryos, which fails to outgrow due to defective FGF10 signaling and lack of activation of FGF-target genes, such as Pea3 and Bmp4 in the epithelium. Specific Hox and Tbx genes may mediate these RA regulatory effects. Development of foregut derivatives can be partly restored in mutants by extending the RA supplementation until at least E10.5, but lung growth and branching remain defective and a hypoplastic lung develops on the right side only. Such conditions poorly restore FGF10 signaling in the lung buds. Explant culture of RALDH2-deficient foreguts show a capacity to undergo lung budding and early branching in the presence of RA or FGF10. Our data implicate RA as a regulator of gene expression in the early embryonic lung and stomach region upstream of Hox, Tbx and FGF10 signaling. (c) 2006 Elsevier Inc. All rights reserved.