Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.
Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.
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DOI：
10.1242/dev.027748
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Izpisua Belmonte JC
中科院分区：
文献类型：
--
作者：
Kawakami Y;Uchiyama Y;Rodriguez Esteban C;Inenaga T;Koyano-Nakagawa N;Kawakami H;Marti M;Kmita M;Monaghan-Nichols P;Nishinakamura R;Izpisua Belmonte JC
在器官发生过程中，在正确的位置以精确的形状产生软骨元件的复杂形态发生的遗传机制，发育生物学中的基本问题，仍然没有得到很好的理解。通过专注于发展中的小鼠肢体，我们确认的重要性，由萨尔基因家族编码的转录因子在适当的肢体形态发生，并进一步表明，他们有重叠的活动，在调节区域形态发生的autopod。Sall 1/Sall 3双无效突变体表现出的digit 1的损失，以及digit 2和digit 3，掌骨和腕骨的损失或融合的autopod。我们发现，萨尔活动影响不同的途径，包括Shh信号通路，以及Hox网络。间充质中的Shh信号传导在萨尔突变肢体中部分受损。此外，我们的数据表明Sall 1-Sall 3和Hoxa 13-Hoxd 13之间存在拮抗作用。我们证明，Epha 3和Epha 4的表达下调Sall 1/Sall 3双无效突变体，相反，上调Hoxa 13和Hoxd 13突变体。此外，Sall 1和Sall 3的表达在Hoxa 13和Hoxd 13突变体中上调。此外，通过使用DNA结合试验，我们表明，萨尔和Hox竞争的目标序列中的Epha 4上游区域。与Shh通路结合，Hoxa 13-Hoxd 13和Sall 1-Sall 3在发育肢体中的拮抗性相互作用可能有助于微调局部Hox活性，从而导致脊椎动物直足动物的每个软骨元件的适当形态发生。
The genetic mechanisms that regulate the complex morphogenesis of generating cartilage elements in correct positions with precise shapes during organogenesis, fundamental issues in developmental biology, are still not well understood. By focusing on the developing mouse limb, we confirm the importance of transcription factors encoded by the Sall gene family in proper limb morphogenesis, and further show that they have overlapping activities in regulating regional morphogenesis in the autopod. Sall1/Sall3 double null mutants exhibit a loss of digit1 as well as a loss or fusion of digit2 and digit3, metacarpals and carpals in the autopod. We show that Sall activity affects different pathways, including the Shh signaling pathway, as well as the Hox network. Shh signaling in the mesenchyme is partially impaired in the Sall mutant limbs. Additionally, our data suggest an antagonism between Sall1-Sall3 and Hoxa13-Hoxd13. We demonstrate that expression of Epha3 and Epha4 is downregulated in the Sall1/Sall3 double null mutants, and, conversely, is upregulated in Hoxa13 and Hoxd13 mutants. Moreover, the expression of Sall1 and Sall3 is upregulated in Hoxa13 and Hoxd13 mutants. Furthermore, by using DNA-binding assays, we show that Sall and Hox compete for a target sequence in the Epha4 upstream region. In conjunction with the Shh pathway, the antagonistic interaction between Hoxa13-Hoxd13 and Sall1-Sall3 in the developing limb may contribute to the fine-tuning of local Hox activity that leads to proper morphogenesis of each cartilage element of the vertebrate autopod.
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影响因子：
2.6
作者：
Buck, A;Kispert, A;Kohlhase, J
通讯作者：
Kohlhase, J
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作者：
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