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- Description
- Phenotype
- Genes & alleles
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Description
The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.
Strain Information
Former Names 129-Madh3tm1Par/J (Changed: 15-DEC-04 ) 129S2/SvPasIco-Madh3tm1Par/J (Changed: 15-DEC-04 ) Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Donating Investigator Luis Parada, UT Southwestern Medical Center Description
Mice homozygous for the targeted mutation are viable. Although fertile, they produce litters at reduced efficacy compared to wild type or heterozygous mice. Null mutants are approximately 20%-30% smaller than heterozygous or wildtype litter mates, with males exhibiting a more pronounced size reduction. Reporter lacZ expression is observed in many developing embryonic tissues with highest levels in mesenchymal derivatives. Expression in adult mutant mice is observed in the colon, with highest levels in the muscularis propria and submucosa with lower levels in the epithelium. At approximately 4-6 months of age, they develop gastric tumors. The donating investigator originally described spontaneous, deeply invasive colorectal adenocarcinomas that penetrate through all layers of the intestinal wall and metastasize to lymph nodes. Colorectal adenocarcinomas are not a component of the phenotype observed in this strain at The Jackson Laboratory. However, the gastric epithelium was found to contain neoplasms that were of a mixed nature. This deviation from the original phenotype may possibly be attributed to differing environmental conditions existing at The Jackson Laboratory facilities and those at the originating institution.Development
This targeted mutation was made in the laboratory of Dr. Luis F. Parada at The University of Texas Southwestern Medical Center. The targeting vector includes a neo cassette and was designed to disrupt the second exon of the locus. In addition, a lacZ gene and an internal ribosomal entry site (IRES) were introduced to permit translation of the beta galactosidase reporter from the interrupted transcript. The IRES-lacZ-neo inserted in the second exon truncates the gene and creates loss-of-function gene product proteins. Alternative splicing around exon 2 shifts the open reading frame. The 129X1/SvJ x 129S1/Sv-dervied R1 ES cell line was used. Chimeric mice carrying the targeted mutation were backcrossed to the 129S2/SvPasIco strain.
Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| Considerations for Choosing Controls | ||
Related Strains
lacZ Expression Strains
View lacZ Expression Strains (186 strains)
Additional Web Information
Fluorescent Proteins/lacZ Systems
Genetic Quality Control Annual Report
New 129 Nomenclature Bulletin
Phenotype
Phenotype Information
assigned by genotype
Smad3tm1Par/Smad3tm1Par
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)
- life span-post-weaning/aging
- premature death (MGI Ref ID J:49839)
- decreased life span; more pronounced in the 129/Sv background than in the mixed 129/Sv and C57BL/6 background, but evident in both
- tumorigenesis
- increased metastatic potential (MGI Ref ID J:49839)
- evidence of metastasis to lymph nodes is seen on the 129/Sv background
- intestinal adenocarcinoma (MGI Ref ID J:49839)
- penetrance of adenocarcinoma is about 30% on the mixed 129/Sv and C57BL/6 background and 100% on the 129/Sv background
- mutants on the mixed background show greater variability in the time course of tumors and tumors are less aggressive and smaller than in the 129/Sv background
- a wide range of tumors are found within a single mouse, including lesions that appear to be polyps
- growth/size phenotype
- decreased body size (MGI Ref ID J:49839)
- about 20% - 30% smaller than controls
- males exhibit a greater size reduction than females
- distended abdomen (MGI Ref ID J:49839)
- due to tumors
- reproductive system phenotype
- abnormal fertility/fecundity (MGI Ref ID J:49839)
- mice are fertile, but have reduced efficacy in producing litters
- behavior/neurological phenotype
- abnormal posture (MGI Ref ID J:49839)
- abnormal, rounded posture, but no associated skeletal defects
- lethargy (MGI Ref ID J:49839)
- as mutants age beyond 18 weeks, they exhibit signs of distress that include lethargy
- digestive/alimentary phenotype
- intestinal obstruction (MGI Ref ID J:49839)
- due to tumors
- rectal prolapse (MGI Ref ID J:49839)
- due to tumors; more pronounced on the 129/Sv background than on the mixed 129/Sv and C57BL/6 background, with 75% of mutants showing prolapse by 24 weeks of age
- skin/coat/nails phenotype
- ruffled hair (MGI Ref ID J:49839)
- as mutants age beyond 18 weeks, they exhibit signs of distress that include fur-ruffling
Smad3tm1Par/Smad3tm1Par
129-Smad3tm1Par/J
- tumorigenesis
- intestinal adenocarcinoma (MGI Ref ID J:106572)
- mutants maintained free of the gram-negative enterohepatic bacteria Helicobacter for up to 9 months do not develop colon cancer as do mutants housed under normal conditions
- infection of mutants with Helicobacter triggers colon cancer in 50-66% of mutants; mucinous adenocarcinomas develop 5 to 30 weeks after infection
- immune system phenotype
- increased inflammatory response (MGI Ref ID J:106572)
- colonic tissue of uninfected mutants is in a proinflammatory state as indicated by increased mRNA levels of IL-6, TNF-alpha, IFN-gamma, and IL-4, which is exacerbated by Helicobacter infection
This mouse can be used to support research in many areas including:
Smad3tm1Par relatedCancer Research
Increased Tumor Incidence
Adenomas: intestinal adenomas
Other Tissues/Organs: GI tract (stomach, intestine, colon)
Other
tumor metastasis
Internal/Organ Research
Gastrointestinal Defects
Reproductive Biology Research
Fertility Defects
Research Tools
lacZ Expression
Cancer Research
tumor immunology
Cancer Research
Increased Tumor Incidence
Other Tissues/Organs: GI tract (stomach, intestine, colon)
Genes & Alleles
Gene & Allele Information
| Allele Symbol | Smad3tm1Par | ||
|---|---|---|---|
| Allele Name | targeted mutation 1, Luis F Parada | ||
| Allele Type | Targeted (Reporter) | ||
| Common Name(s) | Madh3-; Smad3-; Smad3tm1par-; | ||
| Mutation Made By | Luis Parada, UT Southwestern Medical Center | ||
| Strain of Origin | (129X1/SvJ x 129S1/Sv)F1-Kitl<+> | ||
| ES Cell Line Name | R1 | ||
| ES Cell Line Strain | (129X1/SvJ x 129S1/Sv)F1-Kitl<+> | ||
| Site of Expression | lacZ expression is detected in many developing embryonic tissues with high levels detected in mesenchymal derivatives. In adult mice expression is detected in the colon, with highest levels in the muscularis propria and submucosa, lower levels are expressed in the epithelium. | ||
| Gene Symbol and Name | Smad3, MAD homolog 3 (Drosophila) | ||
| Chromosome | 9 | ||
| Gene Common Name(s) | AU022421; DKFZp586N0721; DKFZp686J10186; HSPC193; HsT17436; JV15-2; MADH3; MGC60396; Madh3; Smad 3; expressed sequence AU022421; | ||
| Molecular Note | An IRES-LacZ-neo cassette was inserted into exon 2 of the gene, truncating the carboxyl-terminal active domain of the protein. In addition, this cassette was inserted in a region where point mutations create loss-of-function proteins. Finally, alternative splicing around the disrupted exon would shift the open reading frame. [MGI Ref ID J:49839] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Madh3tm1Par, Standard PCR
Helpful Links
Genotyping resources and troubleshooting
References
References
Selected Reference(s)
Zhu Y; Richardson JA; Parada LF; Graff JM. 1998. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94(6):703-14. [PubMed: 9753318] [MGI Ref ID J:49839]
Additional References
Smad3tm1Par relatedCheon SS; Wei Q; Gurung A; Youn A; Bright T; Poon R; Whetstone H; Guha A; Alman BA. 2006. Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing. FASEB J 20(6):692-701. [PubMed: 16581977] [MGI Ref ID J:129713]
Deane NG; Manning HC; Foutch AC; Washington MK; Aronow BA; Bornhop DJ; Coffey RJ. 2007. Targeted imaging of colonic tumors in smad3-/- mice discriminates cancer and inflammation. Mol Cancer Res 5(4):341-9. [PubMed: 17426249] [MGI Ref ID J:120907]
Domino SE; Karnak DM; Hurd EA. 2007. Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation. Tumour Biol 28(2):77-83. [PubMed: 17264540] [MGI Ref ID J:121796]
Jana S; Jailwala P; Haribhai D; Waukau J; Glisic S; Grossman W; Mishra M; Wen R; Wang D; Williams CB; Ghosh S. 2009. The role of NF-kappaB and Smad3 in TGF-beta-mediated Foxp3 expression. Eur J Immunol 39(9):2571-83. [PubMed: 19701891] [MGI Ref ID J:152150]
Jenkins BJ; Grail D; Nheu T; Najdovska M; Wang B; Waring P; Inglese M; McLoughlin RM; Jones SA; Topley N; Baumann H; Judd LM; Giraud AS; Boussioutas A; Zhu HJ; Ernst M. 2005. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med 11(8):845-52. [PubMed: 16041381] [MGI Ref ID J:100160]
Le AV; Cho JY; Miller M; McElwain S; Golgotiu K; Broide DH. 2007. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. J Immunol 178(11):7310-6. [PubMed: 17513781] [MGI Ref ID J:147829]
Li Q; Graff JM; O'connor AE; Loveland KL; Matzuk MM. 2007. SMAD3 Regulates Gonadal Tumorigenesis. Mol Endocrinol 21(10):2472-86. [PubMed: 17595316] [MGI Ref ID J:125355]
Li Q; Pangas SA; Jorgez CJ; Graff JM; Weinstein M; Matzuk MM. 2008. Redundant roles of SMAD2 and SMAD3 in ovarian granulosa cells in vivo. Mol Cell Biol 28(23):7001-11. [PubMed: 18809571] [MGI Ref ID J:142827]
Looyenga BD; Hammer GD. 2007. Genetic removal of smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery. Mol Endocrinol 21(10):2440-57. [PubMed: 17652186] [MGI Ref ID J:125349]
Maggio-Price L; Treuting P; Bielefeldt-Ohmann H; Seamons A; Drivdahl R; Zeng W; Lai L; Huycke M; Phelps S; Brabb T; Iritani BM. 2009. Bacterial infection of Smad3/Rag2 double-null mice with transforming growth factor-beta dysregulation as a model for studying inflammation-associated colon cancer. Am J Pathol 174(1):317-29. [PubMed: 19119184] [MGI Ref ID J:144197]
Maggio-Price L; Treuting P; Zeng W; Tsang M; Bielefeldt-Ohmann H; Iritani BM. 2006. Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res 66(2):828-38. [PubMed: 16424015] [MGI Ref ID J:106572]
Philipp-Staheli J; Kim KH; Payne SR; Gurley KE; Liggitt D; Longton G; Kemp CJ. 2002. Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice. Cancer Cell 1(4):355-68. [PubMed: 12086850] [MGI Ref ID J:77135]
Romero MI; Lin L; Lush ME; Lei L; Parada LF; Zhu Y. 2007. Deletion of Nf1 in neurons induces increased axon collateral branching after dorsal root injury. J Neurosci 27(8):2124-34. [PubMed: 17314307] [MGI Ref ID J:118374]
Sodir NM; Chen X; Park R; Nickel AE; Conti PS; Moats R; Bading JR; Shibata D; Laird PW. 2006. Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of ApcMin/+ Mice. Cancer Res 66(17):8430-8. [PubMed: 16951153] [MGI Ref ID J:112366]
Tesseur I; Wyss-Coray T. 2006. A role for TGF-beta signaling in neurodegeneration: evidence from genetically engineered models. Curr Alzheimer Res 3(5):505-13. [PubMed: 17168649] [MGI Ref ID J:125213]
Health & husbandry
Health & Colony Maintenance Information
Currently there no information available for this strain. This may be due to the supply level of this strain.
Purchasing information
Pricing, Supply Level & Notes, Controls, General Terms & Conditions
Pricing
| Pricing for USA, Canada and Mexico shipping destinations |
|
Animals Provided
Price (US dollars $) Cryorecovery Fee $1900.00 At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.
Additional Supply Details
| Pricing for International shipping destinations |
|
Animals Provided
Price (US dollars $) Cryorecovery Fee $2470.00 At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.
Additional Supply Details
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Supply Details
| Standard Supply | Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information. |
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| Supply Notes |
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Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 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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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.Ordering and Purchasing Information
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