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首页> 外文期刊>Development >Regionalization of Sonic hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and -independent mechanisms.
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Regionalization of Sonic hedgehog transcription along the anteroposterior axis of the mouse central nervous system is regulated by Hnf3-dependent and -independent mechanisms.

机译：沿小鼠中枢神经系统前后轴的Sonic刺猬转录的区域化受Hnf3依赖性和非依赖性机制调节。

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摘要

The axial midline mesoderm and the ventral midline of the neural tube, the floor plate, share the property of being a source of the secreted protein, Sonic hedgehog (Shh), which has the capacity to induce a variety of ventral cell types along the length of the mouse CNS. To gain insight into the mechanisms by which Shh transcription is initiated in these tissues, we set out to identify the cis-acting sequences regulating Shh gene expression. As an approach, we have tested genomic clones encompassing 35 kb of the Shh locus for their ability to direct a lacZ reporter gene to the temporally and spatially restricted confines of the Shh expression domains in transgenic mice. Three enhancers were identified that directed lacZ expression to distinct regions along the anteroposterior axis including the ventral midline of the spinal cord, hindbrain, rostral midbrain and caudal diencephalon, suggesting that multiple transcriptional regulators are required to initiate Shh gene expression within the CNS. In addition, regulatory sequences were also identified that directed reporter expression to the notochord, albeit, under limited circumstances. Sequence analysis of the genomic clones responsible for enhancer activity from a variety of organisms, including mouse, chicken and human, have identified highly conserved binding sites for the hepatocyte nuclear factor 3 (Hnf3) family of transcriptional regulators in some, but not all, of the enhancers. Moreover, the generation of mutations in the Hnf3-binding sites showed their requirement in certain, but not all, aspects of Shh reporter expression. Taken together, our results support the existence of Hnf3-dependent and -independent mechanisms in the direct activation of Shh transcription within the CNS and axial mesoderm.
机译：神经管的轴向中线中胚层和腹侧中线（底板）具有作为分泌蛋白声波刺猬（Shh）的来源的特性，该蛋白具有沿长度方向诱导多种腹膜细胞类型的能力鼠标中枢神经系统。为了深入了解在这些组织中启动Shh转录的机制，我们着手确定调节Shh基因表达的顺式作用序列。作为一种方法，我们已经测试了包含35 kb Shh基因座的基因组克隆将lacZ报告基因定向到转基因小鼠Shh表达域的时间和空间受限范围内的能力。鉴定出了三种增强子，它们将lacZ表达引导至前后轴的不同区域，包括脊髓的腹中线，后脑，延髓中脑和尾状间脑，这表明在CNS中启动Shh基因表达需要多种转录调节因子。另外，尽管在有限的情况下，也鉴定了将报道基因表达引导至脊索的调控序列。负责分析包括小鼠，鸡和人在内的多种生物的增强子活性的基因组克隆的序列分析，已在一些（但不是全部）人类肝细胞核因子3（Hnf3）转录调节因子家族中确定了高度保守的结合位点。增强子。此外，在Hnf3结合位点的突变的产生表明它们在某些但不是全部Shh报告基因表达方面的需要。两者合计，我们的研究结果支持Hnf3依赖和独立机制在中枢神经系统和轴向中胚层内Shh转录的直接激活中的存在。

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