Cyp26 enzymes function in endoderm to regulate pancreatic field size
Cyp26 enzymes function in endoderm to regulate pancreatic field size
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DOI：
10.1073/pnas.0813108106
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发表时间：
2009-05-12
影响因子：
11.1
通讯作者：
Prince, Victoria E.
中科院分区：
文献类型：
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作者：
Kinkel, Mary D.;Sefton, Elizabeth M.;Prince, Victoria E.
器官大小和位置的控制至少部分依赖于对指定器官祖区的信号的适当调节。胰腺细胞的命运由视黄酸 (RA) 决定，胰腺区域的适当大小和定位取决于 RA 信号传导的严格控制。在这里，我们证明 RA 降解 Cyp26 酶在定义胰野正常前界方面发挥着关键作用。 Cyp26 功能的破坏会导致胰腺细胞类型向胚胎前部急剧扩张。当 RA 发出信号指定胰腺时，cyp26a1 基因在发育阶段的前躯干内胚层中表达，对 cyp26a1/giraffe (gir) 突变体斑马鱼胚胎的分析证实 cyp26a1 在设定胰腺前限中发挥主要作用。对 gir 突变体的分析进一步表明，cyp26b1 和 cyp26c1 功能冗余，以部分补偿 Cyp26a1 功能的丧失。我们使用细胞移植来确定 Cyp26a1 在内胚层中直接发挥作用，调节 RA 信号传导并限制胰腺区域。结合我们发现 cyp26 基因的内胚层表达受到 RA 的正向调节，我们的数据揭示了内胚层内的反馈回路。尽管 RA 浓度存在环境波动，但这种反馈可以维持 RA 信号传导水平的一致，从而确保胰腺区域的大小和位置一致。
The control of organ size and position relies, at least in part, upon appropriate regulation of the signals that specify organ progenitor fields. Pancreatic cell fates are specified by retinoic acid ( RA), and proper size and localization of the pancreatic field are dependent on tight control of RA signaling. Here we show that the RA-degrading Cyp26 enzymes play a critical role in defining the normal anterior limit of the pancreatic field. Disruption of Cyp26 function causes a dramatic expansion of pancreatic cell types toward the anterior of the embryo. The cyp26a1 gene is expressed in the anterior trunk endoderm at developmental stages when RA is signaling to specify pancreas, and analysis of cyp26a1/giraffe (gir) mutant zebrafish embryos confirms that cyp26a1 plays the primary role in setting the anterior limit of the pancreas. Analysis of the gir mutants further reveals that cyp26b1 and cyp26c1 function redundantly to partially compensate for loss of Cyp26a1 function. We used cell transplantation to determine that Cyp26a1 functions directly in endoderm to modulate RA signaling and limit the pancreatic field. Taken together with our finding that endodermal expression of cyp26 genes is subject to positive regulation by RA, our data reveal a feedback loop within the endoderm. Such feedback can maintain consistent levels of RA signaling, despite environmental fluctuations in RA concentration, thus ensuring a consistent size and location of the pancreatic field.