Control of kidney, eye and limb expression of Bmp7 by an enhancer element highly conserved between species
Control of kidney, eye and limb expression of Bmp7 by an enhancer element highly conserved between species
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DOI：
10.1016/j.ydbio.2007.08.036
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发表时间：
2007-11-15
影响因子：
2.7
通讯作者：
Oxburgh, Leif
中科院分区：
文献类型：
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作者：
Adams, Derek;Karolak, Michele;Oxburgh, Leif
BMP7在整个发育过程中在许多组织中表达，并且是眼睛、后肢和肾脏的形态发生所必需的。在这项研究中，我们表明，大多数，如果不是所有的顺式调控序列在这些解剖学位点的表达在发展过程中存在于约20 kb的外显子1周围。在眼睛、四肢和肾脏中，多个不同的增强子元件驱动每个器官内的Bmp7表达。在眼睛中，色素上皮和虹膜中驱动表达的元件在空间上是分离的。在肾脏中，Bmp7在集合管和肾单位祖细胞中的表达由单独的增强子元件驱动。同样，肢体间充质和顶端外胚层嵴的表达是由不同的元素。尽管色素上皮、肾源性间充质和顶端外胚层嵴的增强子分布在大约20 kb的区域内，但内含子1内大约480个碱基对的元件支配发育中的虹膜、肾的集合管系统和肢体间充质内的表达。该元件在不同脊椎动物之间的Bmp7基因座中的序列和位置都非常保守，从热带爪蟾到智人，表明在这些组织部位存在Bmp7表达的强烈选择压力。此外，我们表明青蛙增强子在转基因小鼠中适当地发挥作用。有趣的是，在脊椎动物如斑马鱼和红鳍东方鲀的Bmp7基因中没有发现内含子1元件，这表明Bmp7基因的这种修饰可能是在从水生到陆生的适应过程中出现的。突变分析表明，内含子1元件的增强子活性完全依赖于内含子1增强子内的10个碱基对位点的存在，所述内含子1增强子含有FOXD 3转录因子的预测结合位点。(C)2007年爱思唯尔公司All rights reserved.
Bmp7 is expressed in numerous tissues throughout development and is required for morphogenesis of the eye, hindlimb and kidney. In this study we show that the majority if not all of the cis-regulatory sequence governing expression at these anatomical sites during development is present in approximately 20 kb surrounding exon 1. In eye, limb and kidney, multiple distinct enhancer elements drive Bmp7 expression within each organ. In the eye, the elements driving expression in the pigmented epithelium and iris are spatially separated. In the kidney, Bmp7 expression in collecting ducts and nephron progenitors is driven by separate enhancer elements. Similarly, limb mesenchyme and apical ectodermal ridge expression are governed by separate elements. Although enhancers for pigmented epithelium, nephrogenic mesenchyme and apical ectodermal ridge are distributed across the approximately 20 kb region, an element of approximately 480 base pairs within intron 1 governs expression within the developing iris, collecting duct system of the kidney and limb mesenchyme. This element is remarkably conserved both in sequence and position in the Bmp7 locus between different vertebrates, ranging from Xenopus tropicalis to Homo sapiens, demonstrating that there is strong selective pressure for Bmp7 expression at these tissue sites. Furthermore, we show that the frog enhancer functions appropriately in transgenic inice. Interestingly, the intron 1 element cannot be found in the Bmp7 genes of vertebrates such as Danio rerio and Takifugu rubripes indicating that this modification of the Bmp7 gene might have arisen during the adaptation from aquatic to terrestrial life. Mutational analysis demonstrates that the enhancer activity of the intron 1 element is entirely dependent on the presence of a 10 base pair site within the intron 1 enhancer containing a predicted binding site for the FOXD3 transcription factor. (C) 2007 Elsevier Inc. All rights reserved.