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Dev Biol
2007 Nov 15;3112:679-90. doi: 10.1016/j.ydbio.2007.08.036.
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Control of kidney, eye and limb expression of Bmp7 by an enhancer element highly conserved between species.
Adams D
,
Karolak M
,
Robertson E
,
Oxburgh L
.
???displayArticle.abstract??? 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, limbmesenchyme 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 limbmesenchyme. 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 mice. 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.
Fig. 1. Genomic organization of the murine Bmp7 locus and screening strategy used to identify enhancer elements. (A) The Bmp7 gene is comprised of 7 discrete exons distributed over approximately 72 kb on mouse chromosome 2. Exon–intron structure is depicted, with black boxes corresponding to exons comprising the 5′ UTR and encoding mRNA for the prodomain of BMP7 and red boxes corresponding to exons comprising the 3′ UTR and mRNA for the mature domain of BMP7. Bar at top right represents 2.5 kb. (B) Predicted structures of Bmp7 transcripts based on sequencing of newborn kidney cDNA and 3′ RACE of embryonic kidney mRNA: in addition to the previously published initiation site 102 bp upstream of the first AUG (1.9 and 3.6 kb transcripts), an initiation site was identified 372 bp upstream of the AUG (2.1 and 3.8 kb transcripts). Additionally, two 3′ termini were identified: one 448 bp downstream from the UAG stop codon (1.9 and 2.1 kb transcripts), and another 1887 bp downstream from the UAG (3.6 and 3.8 kb transcripts). Red and black regions correspond to red and black exons in panel A. (C) Total RNA was isolated from E13.5, E17.5 and adult kidneys (13.5, 17.5 and ad respectively), and subjected to Northern hybridization with a probe corresponding to the entire Bmp7 coding sequence. Four RNA species were detected; 1.9 kb, 2.1 kb, 3.6 kb and 3.8 kb. Alternate initiation and termination sites shown in panel B account for these four distinct RNA transcripts. (D) Strategy used to screen for enhancer elements driving Bmp7 expression in the developing kidney. The genomic region surrounding Bmp7 exon 1 (bracketed in panel A) is shown, and lines below denote sizes of genomic subclones 142:1, 216:1, 216:2, 217:1 and 217:2. The presence of enhancer elements in each of these subclones was assayed using the Hsp68lacZpA reporter in transgenic mice. Reporter constructs drive expression at diverse anatomical sites. (E) The 216:2 genomic subclone drives expression in neural crest (NC) adjacent to the neural tube (NT). (F) Expression in nephrogenic mesenchyme (NM) of the kidney is driven by the T fragment. (G, G') Expression in collecting ducts (CD) of the kidney is driven by the 217:1 fragment.
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