Spatiotemporal regulation of GLI target genes in the mammalian limb bud.
Spatiotemporal regulation of GLI target genes in the mammalian limb bud.
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DOI：
10.1016/j.ydbio.2015.07.022
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发表时间：
2015-10-01
影响因子：
2.7
通讯作者：
Vokes SA
中科院分区：
文献类型：
--
作者：
Lewandowski JP;Du F;Zhang S;Powell MB;Falkenstein KN;Ji H;Vokes SA
Gli蛋白以组织特有的方式将Sonic hedgehog(Shh)信号转换为转录输出。Shh途径已经在肢芽中得到了广泛的研究，在那里它通过SHH-FGF反馈环帮助调节生长。然而，转录反应仍然知之甚少。我们通过确定大约200个候选GLI靶基因的基因表达模式来解决这个问题，并确定了三个离散的SHH反应表达区域。在这三个结构域中表达的Gli靶基因主要受GLI3去抑制调控，但对SHH有不同的时间要求。与这些基因相关的GLI结合区既有不同的DNA基序，也有共同的DNA基序。考虑到SHH和成纤维细胞生长因子通路之间相互作用的可能性，我们还测量了GLI靶基因对抑制成纤维细胞生长因子信号通路的反应，发现大多数基因要么不受影响，要么上调。这些结果首次描述了一大组GLI靶基因的时空反应，并为系统水平理解SHH介导的肢体模式背后的基因调控网络奠定了基础。
GLI proteins convert Sonic hedgehog (Shh) signaling into a transcriptional output in a tissue-specific fashion. The Shh pathway has been extensively studied in the limb bud, where it helps regulate growth through a SHH-FGF feedback loop. However, the transcriptional response is still poorly understood. We addressed this by determining the gene expression patterns of approximately 200 candidate GLI-target genes, and identified three discrete SHH-responsive expression domains. GLI-target genes expressed in the three domains are predominately regulated by derepression of GLI3 but have different temporal requirements for SHH. The GLI binding regions associated with these genes harbor both distinct and common DNA motifs. Given the potential for interaction between the SHH and FGF pathways, we also measured the response of GLI-target genes to inhibition of FGF signaling and found the majority were either unaffected or upregulated. These results provide the first characterization of the spatiotemporal response of a large group of GLI-target genes and lay the foundation for a systems-level understanding of the gene regulatory networks underlying SHH-mediated limb patterning.