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| These humanized hCYP1A1_1A2_Cyp1a2/Cyp1a1(-/-) mice may useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for cytochrome P450 family members. | |||||||||
- Description
- Phenotype
- Genes & alleles
- Genotyping
- Health & husbandry
- References
- Purchasing information
- Terms of Use
Description
Strain Information
Former Names B6.Cg-Cyp1a2/Cyp1a1tm2Dwn Tg(CYP1A1,CYP1A2)1Dwn/J (Changed: 29-APR-08 ) B6.Cg-Cyp1a2/Cyp1a1tm1Dwn Tg(CYP1A1-CYP1A2)1Dwn/J (Changed: 17-SEP-07 ) Type Congenic; Mutant Stock; Mutant Strain; Targeted Mutation; Transgenic; Additional information on Genetically Engineered Mutant Mice. Mating System See Colony Maintenance Species laboratory mouse Generation F?+F3 (10-OCT-08) Donating Investigator Daniel Nebert, University of Cincinnati Medical Center Description
Mice homozygous for the Cyp1a2/Cyp1a1(-) targeted allele and carrying the hCYP1A1_1A2 transgene are viable and fertile with normal lifespan. As the Cyp1a2/Cyp1a1(-) targeted allele lacks the coding regions of both Cyp1a1 and Cyp1a2 genes, no expression of either gene transcript or protein is observed in liver or small intestine by quantitative RT-PCR or Western blot, respectively. Transgene expression of the orthologous human genes is observed in the same tissues. While oral benzo[alpha]pyrene (BaP) treatment of Cyp1a2/Cyp1a1(-/-) mutant mice leads to BaP-induced immunosuppression and sickness, the presence of the human CYP1A orthologs in these mice minimizes/prevents such toxicity. These humanized hCYP1A1_1A2_Cyp1a2/Cyp1a1(-/-) mice may useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for cytochrome P450 family members.Development
"Humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice have interchromosal deletion of a segment of mouse chromosome 9 including the majority of the closely-linked Cyp1a2 and Cyp1a1 genes and also harbor a human CYP1A2 and CYP1A1transgene. Generation of these mice required multiple combinations of other targeting strategies. In detail, the Cyp1a2(t) targeted allele was first generated using a targeting vector designed to insert a loxP-flanked PGK-NEO cassette 350 bp downstream of the endogenous stop codon (about 60 bp 3' of exon 7). Following electroporation into 129S6/SvEvTac-derived embryonic stem (ES) cells and ES cell microinjection into C57BL/6 blastocysts, the chimera's were bred with C57BL/6 to generate Cyp1a2(t) mutant mice. To create the Cyp1a1 targeted allele, a targeting vector was designed to insert a loxP-flanked hypoxanthine phosphoribosyltransferase (HPRT) minigene in intron 1 and a loxP site downstream of the termination codon in exon 7. Following electroporation into 129P2/OlaHsd-derived E14TG2a (HPRT-) ES cells, ES cells were microinjected into the blastocoele cavity of C57BL/6J embryos, and chimeric males were bred with C57BL/6J females. These Cyp1a1(t) mutant mice were then bred to a Cre-recombinase strain (CAGGS-CRE, mixed C57BL/6J and FVB/J genetic background). Transgenic offspring found to be heterozygous for the floxed null Cyp1a1(-) allele (containing only exon 1, a portion of intron 1, and one remaining loxP site in the 3' UTR) and hemizygous for CAGGS-CRE were bred to mice heterozygous for the Cyp1a2(t) allele. Mutant mice (Cyp1a2(t), Cyp1a1(-), CAGGS-CRE) were bred to C57BL/6. Because of the close genomic position of these two genes, offspring could be selected which had undergone Cre recombinase-mediated interchromosomal recombination between the loxP sites 3' beyond the stop codons of the Cyp1a2 and Cyp1a1 genes. Such mice were backcrossed to C57BL/6 for 10 generations (while selecting against the Cre transgene) to generate Cyp1a1/1a2 mutant mice. To create "humanized" CYP1A1 and CYP1A2 transgenic mice (hCYP1A1_1A2), a single copy of the 180-kb human CYP1A1_CYP1A2 locus-containing BAC-H (BAC Human CTB clone 31H21: including the 23.3 kb spacer region, 90 kb of CYP1A2 3'-flanking region and 53 kb of CYP1A1 3' flanking region) was microinjected into (C57BL/6JxDBA/2J)F1 oocytes. Founder mice having a single copy of BAC-H were identified and then backcrossed for 10 generations to C57BL/6 mice. These hCYP1A1_1A2 transgenic mice were next bred with Cyp1a1/1a2 mutant mice, generating the final mutant strain; "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice.NOTE: A 22 SNP (single nucleotide polymorphism) panel analysis performed by The Jackson Laboratory revealed that this strain is on a mixed STOCK background (5 out of 22 markers are segregating for C57BL/6, FVB/N, or 129).
Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | (approximate) | |
| Considerations for Choosing Controls | ||
Related Strains
Strains carrying other alleles of CYP1A1
003538 B6.Cg-Tg(APOC2)2Bres/J 002925 B6;CBA-Tg(APOC2)2Bres/J View Strains carrying other alleles of CYP1A1 (2 strains)
002909 129-Cyp1a2tm1Gonz/J
Additional Web Information
Congenic Nomenclature
Phenotype
Phenotype Information
assigned by genotype
Cyp1a2/Cyp1a1tm2Dwn/Cyp1a2/Cyp1a1tm2Dwn Tg(CYP1A1,CYP1A2)1Dwn/Tg(CYP1A1,CYP1A2)1Dwn
B6.Cg-Cyp1a2/Cyp1a1tm2Dwn Tg(CYP1A1,CYP1A2)1Dwn
- liver/biliary system phenotype
- enlarged liver (MGI Ref ID J:122409)
- after oral treatment with 125 mg/kg/day of benzo[a]pyrene BaP, mice show increased liver size
This mouse can be used to support research in many areas including:
Cancer Research
Toxicology
Cell Biology Research
Transcriptional Regulation
Research Tools
Cancer Research
Cell Biology Research
Metabolism Research
Toxicology Research (drug metabolism)
Toxicology Research (drug/compound testing)
Genes & Alleles
Gene & Allele Information
| Allele Symbol | Cyp1a2/Cyp1a1tm2Dwn | ||
|---|---|---|---|
| Allele Name | targeted mutation 2, Daniel W Nebert | ||
| Allele Type | Targeted (knock-out) | ||
| Common Name(s) | Cyp1a1/1a2-/-; | ||
| Strain of Origin | 129P2/OlaHsd and 129S6/SvEvTac | ||
| Gene Symbol and Name | Cyp1a1, cytochrome P450, family 1, subfamily a, polypeptide 1 | ||
| Chromosome | 9 | ||
| Gene Common Name(s) | AHH; AHRR; CP11; CYP1; Cyp45c; Cypc45c; P-450MC; P1-450; P450-1; P450-C; P450DX; cytochrome P450 subfamily I, polypeptide 1; | ||
| Molecular Note | The Cyp1a2(t) targeted allele (J:122409) was generated using a targeting vector designed to insert a loxP-flanked PGK-NEO cassette 350 bp downstream of the endogenous stop codon (about 60 bp 3' of exon 7). The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells which were microinjection into C57BL/6 blastocysts. The chimeras were bred with C57BL/6 to generate Cyp1a2(t) mutant mice. To create the Cyp1a1 targeted allele (J:59398), a targeting vector was designed to insert a loxP-flanked hypoxanthine phosphoribosyltransferase (HPRT) minigene in intron 1 and a loxP site downstream of the termination codon in exon 7. Following electroporation into E14TG2a (HPRT-) ES cells and ES cell microinjection into the blastocoele cavity of C57BL/6J embryos, chimeric males were bred with C57BL/6J females. As described in J:86748, these Cyp1a1(t) mutant mice were then bred to a Cre-deleter strain (CAGGS-CRE, mixed C57BL/6J and FVB/NJ genetic background). The resulting transgenic mice found tobe heterozygous for the floxed null Cyp1a1(-) allele (containing only exon 1, a portion of intron 1, and one remaining loxP site in the 3' UTR) were bred to mice heterozygous for the Cyp1a2(t) allele (as described in J:122409). Mutant mice (Cyp1a2(t), Cyp1a1(-), CAGGS-CRE) were bred to C57BL/6. Because of the close genomic position of these two genes, offspring having undergone Cre recombinase-mediated interchromosomal recombination between the loxP sites 3' beyond the stop codons of the Cyp1a2 and Cyp1a1 genes could be selected. Such mice were backcrossed to C57BL/6 for 10 generations (while selecting against the Cre-deleter transgene) to generate Cyp1a1/1a2 mutant mice. [MGI Ref ID J:122409] [MGI Ref ID J:59398] [MGI Ref ID J:86748] | ||
| Allele Symbol | Cyp1a2/Cyp1a1tm2Dwn | ||
| Allele Name | targeted mutation 2, Daniel W Nebert | ||
| Allele Type | Targeted (knock-out) | ||
| Common Name(s) | Cyp1a1/1a2-/-; | ||
| Strain of Origin | 129P2/OlaHsd and 129S6/SvEvTac | ||
| Gene Symbol and Name | Cyp1a2, cytochrome P450, family 1, subfamily a, polypeptide 2 | ||
| Chromosome | 9 | ||
| Gene Common Name(s) | CP12; CYPD45; P-450d; P3-450; P450(PA); P450-3; RATCYPD45; aromatic compound inducible; | ||
| Molecular Note | The Cyp1a2(t) targeted allele (J:122409) was generated using a targeting vector designed to insert a loxP-flanked PGK-NEO cassette 350 bp downstream of the endogenous stop codon (about 60 bp 3' of exon 7). The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells which were microinjection into C57BL/6 blastocysts. The chimeras were bred with C57BL/6 to generate Cyp1a2(t) mutant mice. To create the Cyp1a1 targeted allele (J:59398), a targeting vector was designed to insert a loxP-flanked hypoxanthine phosphoribosyltransferase (HPRT) minigene in intron 1 and a loxP site downstream of the termination codon in exon 7. Following electroporation into E14TG2a (HPRT-) ES cells and ES cell microinjection into the blastocoele cavity of C57BL/6J embryos, chimeric males were bred with C57BL/6J females. As described in J:86748, these Cyp1a1(t) mutant mice were then bred to a Cre-deleter strain (CAGGS-CRE, mixed C57BL/6J and FVB/NJ genetic background). The resulting transgenic mice found tobe heterozygous for the floxed null Cyp1a1(-) allele (containing only exon 1, a portion of intron 1, and one remaining loxP site in the 3' UTR) were bred to mice heterozygous for the Cyp1a2(t) allele (as described in J:122409). Mutant mice (Cyp1a2(t), Cyp1a1(-), CAGGS-CRE) were bred to C57BL/6. Because of the close genomic position of these two genes, offspring having undergone Cre recombinase-mediated interchromosomal recombination between the loxP sites 3' beyond the stop codons of the Cyp1a2 and Cyp1a1 genes could be selected. Such mice were backcrossed to C57BL/6 for 10 generations (while selecting against the Cre-deleter transgene) to generate Cyp1a1/1a2 mutant mice. [MGI Ref ID J:122409] [MGI Ref ID J:59398] [MGI Ref ID J:86748] | ||
| Allele Symbol | Tg(CYP1A1,CYP1A2)1Dwn | ||
| Allele Name | transgene insertion 1, Daniel W Nebert | ||
| Allele Type | Transgenic (random, expressed) | ||
| Common Name(s) | hCYP1A1_1A2, BAC-H; | ||
| Strain of Origin | (C57BL/6J x DBA/2J)F1 | ||
| Expressed Gene | CYP1A2, cytochrome P450, family 1, subfamily A, polypeptide 2, human | ||
| Expressed Gene | CYP1A1, cytochrome P450, family 1, subfamily A, polypeptide 1, human | ||
| Promoter | CYP1A2, cytochrome P450, family 1, subfamily A, polypeptide 2, human | ||
| Promoter | CYP1A1, cytochrome P450, family 1, subfamily A, polypeptide 1, human | ||
| Molecular Note | To create "humanized" CYP1A1 and CYP1A2 transgenic mice (hCYP1A1_1A2), a single copy of the 180-kb human CYP1A1_CYP1A2 locus-containing BAC-H (BAC Human CTB clone 31H21: including the 23.3 kb spacer region, 90 kb of CYP1A2 3'-flanking region and 53 kb ofCYP1A1 3' flanking region) was microinjected into (C57BL/6J x DBA/2J)F1 oocytes. Founder mice having a single copy of BAC-H were identified and then backcrossed for 10 generations to C57BL/6 mice. [MGI Ref ID J:96716] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Tg(CYP1A1,CYP1A2)1Dwn, QPCR, vers. 1
Cyp1a2/Cyp1a1tm2Dwn, STD PCR, vers. 1
Tg(Cyp1a1), STD PCR, vers. 1
Tg(Cyp1a2), STD PCR, vers. 1
Helpful Links
Optimizing PCR Protocols
References
References
Selected Reference(s)
Dalton TP; Dieter MZ; Matlib RS; Childs NL; Shertzer HG; Genter MB; Nebert DW. 2000. Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem Biophys Res Commun 267(1):184-9. [PubMed: 10623596] [MGI Ref ID J:59398]
Dragin N; Uno S; Wang B; Dalton TP; Nebert DW. 2007. Generation of 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(-/-) mouse line. Biochem Biophys Res Commun 359(3):635-42. [PubMed: 17560947] [MGI Ref ID J:122409]
Jiang Z; Dalton TP; Jin L; Wang B; Tsuneoka Y; Shertzer HG; Deka R; Nebert DW. 2005. Toward the evaluation of function in genetic variability: characterizing human SNP frequencies and establishing BAC-transgenic mice carrying the human CYP1A1_CYP1A2 locus. Hum Mutat 25(2):196-206. [PubMed: 15643613] [MGI Ref ID J:96716]
Uno S; Wang B; Shertzer HG; Nebert DW; Dalton TP. 2003. Balancer-Cre transgenic mouse germ cells direct the incomplete resolution of a tri-loxP-targeted Cyp1a1 allele, producing a conditional knockout allele. Biochem Biophys Res Commun 312(2):494-9. [PubMed: 14637164] [MGI Ref ID J:86748]
Health & husbandry
Health & Colony Maintenance Information
Animal Health Reports
Room Number AX12
Colony Maintenance
Breeding & Husbandry When maintaining a live colony, these mice (homozygous for the Cyp1a1/1a2 targeted allele and hemizygous for the hCYP1A1_1A2 transgene) may be bred together. Mating System See above Diet Information LabDiet® 5K52/5K67
Purchasing information
Pricing, Supply Level & Notes, Controls, General Terms & Conditions
Pricing
| Pricing for USA, Canada and Mexico shipping destinations |
|
Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $236.40 Female or Male Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $472.80 Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn x Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn
Additional Supply Details
| Supply Notes |
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| Pricing for International shipping destinations |
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Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $307.40 Female or Male Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $614.70 Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn x Homozygous for Cyp1a2/Cyp1a1tm2Dwn, Homozygous or Hemizygous for Tg(CYP1A1,CYP1A2)1Dwn
Additional Supply Details
| Supply Notes |
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Supply Details
| Standard Supply | Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement. |
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| Supply Notes |
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Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | (approximate) | |
| Considerations for Choosing Controls | ||
| USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains. | ||
| International - Control Pricing Information for Genetically Engineered Mutant Strains. | ||
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