Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut
Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut
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DOI：
10.1016/j.ydbio.2004.04.039
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发表时间：
2004-09-15
影响因子：
2.7
通讯作者：
Cardoso, WV
中科院分区：
文献类型：
--
作者：
Desai, TJ;Malpel, S;Cardoso, WV
虽然维甲酸（RA）信号中断导致的呼吸道缺陷已被广泛报道，但内源性RA调节早期肺形态发生的机制尚不清楚。在这里，我们提供了新的证据，表明RA的主要作用是选择性地维持中胚层增殖，并诱导肺形成的前肠区域的成纤维细胞生长因子10 （Fgf10）表达。通过在前肠外植体培养中使用泛rar拮抗剂（BMS493），我们发现由于Fgf10在相应的中胚层中诱导失败，在预期的呼吸区萌发被选择性地阻断。RA对Fgf10表达的调节仅发生在该区域，在一个确定的发育窗口内，而在其他前肠衍生物如甲状腺和胰腺中未见，其中Fgf10也是正常发育所必需的。此外，我们发现RA活性对于维持肺内胚层的肺细胞特性至关重要；RAR拮抗可破坏甲状腺转录因子1 （Ttf1）和表面活性剂蛋白C (Sp-C) mrna的表达，Ttf1是内皮层呼吸区早期标志物。我们在小鼠前肠培养中的观察结果得到了大鼠体内维生素A缺乏症模型数据的证实。我们的研究支持RA是初芽形成过程中基因表达和细胞活动的重要调节因子。(C) 2004爱思唯尔公司版权所有。
Although respiratory tract defects that result from disruption of retinoic acid (RA) signaling have been widely reported, the mechanism by which endogenous RA regulates early lung morphogenesis is unknown. Here, we provide novel evidence that a major role for RA is to selectively maintain mesodermal proliferation and induce fibroblast growth factor 10 (Fgf10) expression in the foregut region where the lung forms. By using a pan-RAR antagonist (BMS493) in foregut explant cultures, we show that bud initiation is selectively blocked in the prospective respiratory region by failure to induce Fgf10 in the corresponding mesoderm. The RA regulation of Fgf10 expression occurs only in this region, within a defined developmental window, and is not seen in other foregut derivatives such as thyroid and pancreas where Fgf10 is also required for normal development. Furthermore, we show that RA activity is essential in the lung field to maintain lung cell identity in the endoderm; RAR antagonism disrupts expression of thyroid transcription factor 1 (Ttf1), an early marker of the respiratory region in the endoderm, and surfactant protein C (Sp-C) mRNAs. Our observations in mouse foregut cultures are corroborated by data from an in vivo model of vitamin A deficiency in rats. Our study supports RA as an essential regulator of gene expression and cellular activities during primary bud formation. (C) 2004 Elsevier Inc. All rights reserved.