Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development
Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development
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DOI：
10.1242/dev.02706
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发表时间：
2007-01-01
期刊：
影响因子：
4.6
通讯作者：
Moens, Cecilia B.
中科院分区：
文献类型：
--
作者：
Hernandez, Rafael E.;Putzke, Aaron P.;Moens, Cecilia B.
视黄酸（RA）对脊椎动物的正常发育至关重要，包括中枢神经系统的形成。在早期胚胎发生过程中，RA通过母体饮食中维生素A的代谢在躯干中胚层产生，并在发育中的后脑中作为形态因子，在那里它指定Hox基因表达的巢状结构域。内源性RA源的丧失可以通过使用均匀浓度的外源性RA治疗来恢复，这表明RA的反应性域可以由其他机制形成，而不仅仅是局部后源的RA扩散。在这里，我们发现Cyp26类的细胞色素p450酶，将RA代谢成极性衍生物，在后脑发育过程中发挥冗余功能，形成RA依赖的基因表达域。在缺乏三个哺乳动物CYP26基因CYP26A1、CYP26B1和CYP26C1同源基因的斑马鱼胚胎中，整个后脑表达了通常局限于后脑后部巢状结构域的ra -应答基因。此外，我们发现Cyp26酶对于外源性RA在RA耗尽的胚胎中拯救后脑模式是必不可少的。我们提出了一个“无梯度”的后脑模式模型，其中沿后脑前后轴的不同RA反应性主要由RA降解酶的动态表达形成。
Retinoic acid ( RA) is essential for normal vertebrate development, including the patterning of the central nervous system. During early embryogenesis, RA is produced in the trunk mesoderm through the metabolism of vitamin A derived from the maternal diet and behaves as a morphogen in the developing hindbrain where it specifies nested domains of Hox gene expression. The loss of endogenous sources of RA can be rescued by treatment with a uniform concentration of exogenous RA, indicating that domains of RA responsiveness can be shaped by mechanisms other than the simple diffusion of RA from a localized posterior source. Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development. In zebrafish embryos depleted of the orthologs of the three mammalian CYP26 genes CYP26A1, CYP26B1 and CYP26C1, the entire hindbrain expresses RA-responsive genes that are normally restricted to nested domains in the posterior hindbrain. Furthermore, we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos. We present a 'gradient-free' model for hindbrain patterning in which differential RA responsiveness along the hindbrain anterior-posterior axis is shaped primarily by the dynamic expression of RA-degrading enzymes.