A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain
A highly conserved enhancer in the Dlx5/Dlx6 intergenic region is the site of cross-regulatory interactions between Dlx genes in the embryonic forebrain
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DOI：
10.1523/jneurosci.20-02-00709.2000
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发表时间：
2000-01-15
影响因子：
5.3
通讯作者：
Ekker, M
中科院分区：
文献类型：
--
作者：
Zerucha, T;Stühmer, T;Ekker, M
四个DLX同源框基因Dlx1、Dlx2、Dlx5和Dlx6在小鼠前脑的同一原基中表达，具有时间重叠的模式。这四个基因被组织成两个尾巴对，Dlx1/Dlx2和Dlx5/Dlx6，这是一种在斑马鱼等远亲脊椎动物中保守的基因组排列。Dlx5/Dlx6基因间隔区包含两个几百个碱基对的序列，在老鼠和斑马鱼之间非常保守。含有这两个序列的报告基因在转基因小鼠和斑马鱼的前脑中表达，其模式与内源性Dlx5和Dlx6的表达模式高度相似。在同时缺乏Dlx1和Dlx2的小鼠突变体中，转基因活性显著降低，这与内源性Dlx5和Dlx6表达的减少一致。这些结果表明，Dlx5和Dlx6在前脑中的表达是由基因间序列介导的DLX蛋白的交叉调节所致。这一假说得到了共转染和DNA-蛋白质结合实验的支持。我们认为DLX基因是调节前脑发育的高度保守的发育途径的一部分。
Four Dlx homeobox genes, Dlx1, Dlx2, Dlx5, and Dlx6 are expressed in the same primordia of the mouse forebrain with temporally overlapping patterns. The four genes are organized as two tail-to-tail pairs, Dlx1/Dlx2 and Dlx5/Dlx6, a genomic arrangement conserved in distantly related vertebrates like zebrafish. The Dlx5/Dlx6 intergenic region contains two sequences of a few hundred base pairs, remarkably well conserved between mouse and zebrafish. Reporter transgenes containing these two sequences are expressed in the forebrain of transgenic mice and zebrafish with patterns highly similar to endogenous Dlx5 and Dlx6 expression. The activity of the transgene is drastically reduced in mouse mutants lacking both Dlx1 and Dlx2, consistent with the decrease in endogenous Dlx5 and Dlx6 expression. These results suggest that cross-regulation by Dlx proteins, mediated by the intergenic sequences, is essential for Dlx5 and Dlx6 expression in the forebrain. This hypothesis is supported by cotransfection and DNA-protein binding experiments. We propose that the Dlx genes are part of a highly conserved developmental pathway that regulates forebrain development.