Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish
Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish
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DOI：
10.1242/dev.077065
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发表时间：
2012-06-15
期刊：
影响因子：
4.6
通讯作者：
Schilling, Thomas F.
中科院分区：
文献类型：
--
作者：
Cai, Anna Q.;Radtke, Kelly;Schilling, Thomas F.
维生素A衍生物维甲酸(RA)是脊椎动物后脑前后轴的一种形态生成物。细胞维甲酸结合蛋白(CRABPS)在细胞内将RA转运到其核受体(RARs)和降解酶(Cyp26s)。然而，缺乏Crabp的小鼠是可行的，这表明Crabp的功能与其他脂肪酸结合蛋白的功能是多余的。在这里，我们展示了斑马鱼中的Crabp对于后脑的后脑模式是必不可少的，并且它们提供了一种关键的反馈机制，使信号变得强大，因为它们能够补偿RA产生的变化。在四种斑马鱼Crabp2a中，Crabp2a是唯一可诱导RA的基因，Crabp2a的缺失或过表达使胚胎对外源RA高度敏感。计算模型证实，Crabp2a在一个狭窄的浓度范围内提高了稳健性，从而整合了沿RA形态梯度的空间信息，从而优化了“稳健性指数”。对我们模型中的信号参数的探索表明，Crabp2a将RA运输到Cyp26酶进行降解的能力是促进稳健性的主要因素。这些结果证明了CRABPS在RA信号转导和后脑发育中的未知要求，以及一种新的稳定形态原梯度的机制，尽管遗传或环境在形态原可获得性方面存在波动。
The vitamin A derivative retinoic acid (RA) is a morphogen that patterns the anterior-posterior axis of the vertebrate hindbrain. Cellular retinoic acid-binding proteins (Crabps) transport RA within cells to both its nuclear receptors (RARs) and degrading enzymes (Cyp26s). However, mice lacking Crabps are viable, suggesting that Crabp functions are redundant with those of other fatty acid-binding proteins. Here we show that Crabps in zebrafish are essential for posterior patterning of the hindbrain and that they provide a key feedback mechanism that makes signaling robust as they are able to compensate for changes in RA production. Of the four zebrafish Crabps, Crabp2a is uniquely RA inducible and depletion or overexpression of Crabp2a makes embryos hypersensitive to exogenous RA. Computational models confirm that Crabp2a improves robustness within a narrow concentration range that optimizes a 'robustness index', integrating spatial information along the RA morphogen gradient. Exploration of signaling parameters in our models suggests that the ability of Crabp2a to transport RA to Cyp26 enzymes for degradation is a major factor in promoting robustness. These results demonstrate a previously unrecognized requirement for Crabps in RA signaling and hindbrain development, as well as a novel mechanism for stabilizing morphogen gradients despite genetic or environmental fluctuations in morphogen availability.