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Gene
2006 Aug 01;377:46-55. doi: 10.1016/j.gene.2006.03.010.
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ACE2 orthologues in non-mammalian vertebrates (Danio, Gallus, Fugu, Tetraodon and Xenopus).
Chou CF
,
Loh CB
,
Foo YK
,
Shen S
,
Fielding BC
,
Tan TH
,
Khan S
,
Wang Y
,
Lim SG
,
Hong W
,
Tan YJ
,
Fu J
.
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Angiotensin-converting enzyme 2 (ACE2), a newly identified member in the renin-angiotensin system (RAS), acts as a negative regulator of ACE. It is mainly expressed in cardiac blood vessels and the tubular epithelia of kidneys and abnormal expression has been implicated in diabetes, hypertension and heart failure. The mechanism and physiological function of this zinc metallopeptidase in mammals are not yet fully understood. Non-mammalian vertebrate models offer attractive and simple alternatives that could facilitate the exploration of ACE2 function. In this paper we report the in silico analysis of Ace2 genes from the Gallus (chicken), Xenopus (frog), Fugu and Tetraodon (pufferfish) genome assembly databases, and from the Danio (zebrafish) cDNA library. Exon ambiguities of Danio and Xenopus Ace2s were resolved by RT-PCR and 3'RACE. Analyses of the exon-intron structures, alignment, phylogeny and hydrophilicity plots, together with the conserved synteny among these vertebrates, support the orthologous relationship between mammalian and non-mammalian ACE2s. The putative promoters of Ace2 from human, Tetraodon and Xenopus tropicalis drove the expression of enhanced green fluorescent protein (EGFP) specifically in the heart tissue of transgenic Xenopus thus making it a suitable model for future functional genomic studies. Additionally, the search for conserved cis-elements resulted in the discovery of WGATAR motifs in all the putative Ace2 promoters from 7 different animals, suggesting a possible role of GATA family transcriptional factors in regulating the expression of Ace2.
Fig. 1.
Ace2–Nhs loci of human (chromosome [chr] X), chicken (chr 1), Xenopus (scaffold 403, 38 and 56), Fugu (scaffold 2251) and Tetraodon (chr 5). Genes and their orientations are shown as arrows. The dashed line in Xenopus locus indicates the discontinuity and distinguishes the three scaffolds. The gene orders were obtained from the UCSC Genome Browsers (http://genome.ucsc.edu). Locus positions in the chromosome or scaffold are underlined.
Fig. 2.
The hydrophilicity plots for ACE2s from human, mouse, chicken, Xenopus, Fugu, Tetraodon and zebrafish generated using Kyte and Doolittle hydrophilicity parameters. The location of the N-terminal amino acid (a.a.) residue of the mature ACE2s is indicated by arrows. Full-size image (<1 K) denotes the transmembrane domains.
Fig. 3.
The phylogenetic analysis of the ACE2 protein sequences, obtained using the program MegAlign with the default ClustalW parameters. The source of ACE2s and ACEs are prefixed by h (human), m (mouse), g (chicken), x (Xenopus), f (Fugu), t (Tetraodon) and z (zebrafish).
Fig. 4.
Ace2 promoters drive the tissue specific expression of EGFP on the heart surface of transgenic Xenopus. (A) The expression was driven by 0.5 kb Xenopus Ace2 promoter region (lower panels) and 0.6 kb human Ace2 promoter region (upper panels). EGFP was visualized using a fluorescent microscope. The left panels were photos taken under brightfield and the right panels were taken under settings for EGFP fluorescence. The ventricle is shown by arrows and the truncus arteriosis by arrow heads. Dashed arrows indicate nonspecific fluorescence from GI tracts. (B) Fluorescenced hearts of transgenic Xenopus using the putative promoter of Tetraodon are shown and indicated by arrows. Photos were taken under filtered UV and dimmed light for presenting the fluorescenced heart in entire tadpoles.
Fig. 5.
Seven Ace2 ATG codon upstream sequences from around nt − 640 to − 230 are shown. Sequences shown in bold are potential GATA binding sites. The source of Ace2s are prefixed by h (human), m (mouse), g (gallus), x (Xenopus), f (Fugu), t (Tetraodon) and z (zebrafish).
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