The regulation of membrane cofactor protein (CD46) expression in transgenic mice: The importance of the first 125 BP of the 3′ untranslated region

Miyagawa, Shuji; Ikawa, Masahito; Kominami, Katsuya; Tanaka, Hiromitsu; Mikata, Shoki; Matsuda, Hikaru; Seya, Tsukasa; Shirakura, R; Okabe, Masaru

doi:10.1016/s0041-1345(96)00266-7

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…Several groups have tried to create transgenic pigs or mice with high CD46 expression using minigenes or cDNA constructs (Yannoutsos et al, 1995;Mulder et al, 1997;Mora et al, 1996;Miyagawa et al, 1997), but achieving ubiquitous high expression has been very difficult. One pig line has however been reported as expressing abundant and ubiquitous expression of CD46, from a minigene, and this prevented hyperacute kidney rejection in non-immunosuppressed baboons for several days even without GGTA1 inactivation (Loveland et al, 2004).…”

Section: Cd46mentioning

confidence: 99%

Multi‐transgenic pigs for xenotransplantation

Fischer

Kraner-Scheiber

Flisikowski

et al. 2013

Xenotransplantation

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Genetically modified pigs offer a solution to the severe shortage of organs available for human transplantation. Inactivation of the α1,3‐galactosyltransferase gene, responsible for α1,3‐Gal epitope synthesis (1–2) was a major breakthrough and essentially solved the problem of hyperacute rejection. However, further modifications of donor pigs are required to enable long term xenograft survival. These include expression of complement regulatory, antithrombotic, endothelium protective and immuno‐regulatory transgenes. Current evidence indicates that complement regulator transgenes, such as CD46 and CD55, must be expressed at least fivefold more than their human endogenous equivalent to effectively protect grafted tissue (3). To explore means of achieving high expression, we produced a series of BAC‐ and PAC‐vector constructs containing different sized genomic complement regulatory genes, from 70 to 190 kb, under the control of endogenous or CAGGs (CMV enhancer chicken β actin) promoter sequences. Using these vectors we obtained high levels of CD46 and CD55 expression in vitro. To prepare multi‐transgene “packages” for introduction into animals, the most effective constructs were combined with one or two further xenoprotective transgenes, including A20 (4), HO‐1 (5), thrombomodulin (6) and CTLA4‐Ig (LEA 29Y). In cotransfection experiments single cell clones expressing up to five different xenogenes could be detected. Achieving desired levels of transgene expression in an animal is not only a function of the transgene construct, but also of the location at which it integrates. Position effect variation in expression of random transgenes is well‐documented. Transgene placement by gene targeting at a permissive locus offers a useful means of achieving reliable transgene expression. In mice the ROSA26 locus is widely used to support ubiquitous expression of inserted transgenes (7–8). Murine ROSA26 encodes no functional genes and extensive gene targeting of this locus has not led to deleterious effects on development or physiology (9). To enable a similar approach in pigs, we recently identified a strong candidate for the porcine ROSA26 locus. Gene targeted placement of a neomycin reporter gene construct under the control of the ROSA26 promoter showed expression in all examined porcine tissues of all three germ layers. This strongly suggests that porcine ROSA 26 may resemble the murine locus as a suitably permissive site for transgene expression. We are currently proceeding with gene targeting to place various xenoprotective transgene constructs at this locus. References: 1. Dai Y, Vaught TD, Boone J et al. Targeted disruption of the alpha1,3‐ galactosyltransferase gene in cloned pigs. Nat Biotechnol 2002; 20: 251–255. 2. Lai L, Kolber‐Simonds D, Park K et al. Production of alpha‐1,3‐galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002; 295: 1089–1092. 3. Miyagawa S, Fukuta D, Kitano E et al. Effect of tandem forms of DAF(CD55) on complement‐mediated xenogeneic cell lysis. Xenotransplantation 20...

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Section: Cd46mentioning

confidence: 99%

Multi‐transgenic pigs for xenotransplantation

Fischer

Kraner-Scheiber

Flisikowski

et al. 2013

Xenotransplantation

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“…This is not to say that transcription is the only way in which MCP expression is controlled. There is evidence that sequences in the 3 0 untranslated region control protein expression as well [60,61].…”

Section: Membrane Cofactor Protein (Mcp Cd46)mentioning

confidence: 99%

Transcriptional control of complement receptor gene expression

Martin

2007

Immunol Res

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Immune complement is a critical system in the immune response and protection of host cells from damage by complement is critical during inflammation. The expression of the receptors for the inflammatory anaphylatoxin molecules is also key in immunity. In order to fully appreciate the biology of complement, a basic understanding of the molecular regulation of complement receptor gene expression is critical, yet these kinds of studies are lacking for many genes. Importantly, recent genetic studies have demonstrated that promoter-enhancer polymorphisms can contribute to pathology in diseases such as atypical hemolytic uremic syndrome. This review will focus on what is currently known about the genetic regulation of key protective complement receptors genes including CR1 (CD35), CR2 (CD21), Crry, MCP (CD46), DAF (CD55), and CD59. In addition, the regulation of the anaphylatoxin receptors genes, C3aR and C5aR (CD88) will also be discussed. Since new research continuously uncovers novel functions for these proteins, a greater appreciation of the mechanisms involved in gene regulation will be critical for understanding the biology of these molecules.

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“…Therefore, we set out to identify whether distribution and potency of rAd35 vectors differ in mice carrying the CD46 receptor or wild-type (Wt) littermates. Since the human CD46 protein (hCD46) serves as a high-affinity receptor for several important pathogens including Measles virus (Dorig et al, 1993;Manchester et al, 1994;Naniche et al, 1993), Human herpesvirus 6 (Santoro et al, 1999), Streptococcus pyogenes (Okada et al, 1995), Neisseria gonorrhoeae and Meningitides (Kallstrom et al, 1997), different CD46 transgenic mice models have been generated and studied (Horvat et al, 1996;Miyagawa et al, 1997;Rall et al, 1997;Thorley et al, 1997). In choosing among different CD46 transgenic mouse models, we decided on MYII mice, which were obtained by transferring a 420 kilobase yeast artificial chromosome clone carrying the hCD46 gene under its own regulatory sequences (Yannoutsos et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors

Verhaagh

Jong

Goudsmit

et al. 2006

Journal of General Virology

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Wild-type strains of mice do not express CD46, a high-affinity receptor for human group B adenoviruses including type 35. Therefore, studies performed to date in mice using replication-incompetent Ad35 (rAd35) vaccine carriers may underestimate potency or result in altered vector distribution. Here, it is reported that CD46 transgenic mice (MYII-strain) express CD46 in all major organs and that it functions as a receptor for rAd35 vectors. Similar to monkeys and humans, MYII mice highly express CD46 in their lungs and kidneys and demonstrate low expression in muscle. Upon intravenous administration, rAd35 vector genomes as well as expression are detected in lungs of MYII mice, in contrast to wild-type littermates. Expression was predominantly detected in lung epithelial cells. Upon intramuscular administration, the initial level of luciferase expression is higher in MYII mice as compared with wild-type littermates, in spite of the fact that CD46 expression is low in muscle of MYII mice. The higher level of expression in muscle of MYII mice results in prolonged gene expression as assessed by CCD camera imaging for luciferase activity. Finally, a significant dose-sparing effect in MYII mice as compared with wild-type littermates on anti-SIVgag CD8 + T-cell induction following intramuscular vaccination with an rA35.SIVgag vaccine was observed. This dose-sparing effect was also observed when reinfusing dendritic cells derived from MYII mice after exposure to rAd35.SIVgag vaccine as compared with rAd35.SIVgag exposed dendritic cells from wild-type littermates. It was concluded that MYII mice represent an interesting preclinical model to evaluate potency and safety of rAd35 vectors.

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The regulation of membrane cofactor protein (CD46) expression in transgenic mice: The importance of the first 125 BP of the 3′ untranslated region

Cited by 6 publications

References 5 publications

Multi‐transgenic pigs for xenotransplantation

Multi‐transgenic pigs for xenotransplantation

Transcriptional control of complement receptor gene expression

Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors

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