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Type Congenic; Mutant Strain; Targeted Mutation; Mating System Homozygote x Homozygote (Female x Male) Species laboratory mouse Generation ?+F4 (29-APR-08) Donating Investigator Jack Lawler, Beth Israel Deaconess Medical Center Description
Mice homozygous for this targeted mutation are viable and fertile, with an approximate 20% decrease in embryo/neonate viability and a mild and variable lordotic curvature of the spine apparent from birth. Homozygous mice have an abnormal, but no full length transcript in multiple tissues. Western analysis confirmed the absence of the protein in platelets. Homozygotes exhibit an increase in the number of circulating white blood cells. During the first four to ten weeks of life, homozygotes exhibit patches of acute and organizing pneumonia. At later time points, there is considerable hyperplasia of the various epithelial cell lineages. Mutant mice also have an increased number of retinal endothelial cells and inappropriate remodeling and maturation of retinal vasculature following injury. On the FVB/N background, spontaneous tumor growth and vasculature are significantly increased compared to wildtype. Mutant mice may be useful in studies of inflammatory responses in the lungs, eye, and skin, angiogenesis and vascular pathophysiology, cancer, chemotherapy, apoptosis, and cell differentiation and migration.Development
A targeting vector was designed to replace exon 2, intron 3, and exon 3 of the endogenous gene with a phosphoglycerate kinase–neomycin resistance cassette (PGK-neo) cassette. This construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. Chimeric males were bred with C57BL/6J females. Mutant mice were backcrossed to C57BL/6J for 8 generations prior to sending to The Jackson Laboratory.
| Control | ||
|---|---|---|
| 000664 C57BL/6J | ||
| Considerations for Choosing Controls | ||
Congenic Nomenclature
Mammalian Phenotype Terms assigned by genotype
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Thbs1tm1Hyn/Thbs1tm1Hyn
either: (involves: 129S2/SvPas * 129/Sv) or (involves: 129S2/SvPas * C57BL/6)
- lethality-prenatal/perinatal
- prenatal lethality (MGI Ref ID J:46182)
- fewer than expected number of homozygous mutant mice born after heterozygous matings
- incomplete penetrance
- cardiovascular system phenotype
- abnormal artery morphology (MGI Ref ID J:48446)
- bronchiolar arteries thickened, tortuous, with smooth muscle cell hyperplasia
- abnormal heart ventricle morphology (MGI Ref ID J:48446)
- abnormal ventricular septum morphology (MGI Ref ID J:48446)
- enlarged myocytes within ventricular septum
- lung hemorrhage (MGI Ref ID J:48446)
- into alveoli
- vascular smooth muscle cell hyperplasia (MGI Ref ID J:48446)
- digestive/alimentary phenotype
- abnormal pancreas morphology (MGI Ref ID J:48446)
- increased vascularity
- esophagogastric junction metaplasia (MGI Ref ID J:48446)
- pancreas inflammation (MGI Ref ID J:48446)
- stomach epithelial hyperplasia (MGI Ref ID J:48446)
- endocrine/exocrine gland phenotype
- abnormal pancreas morphology (MGI Ref ID J:48446)
- increased vascularity
- pancreas inflammation (MGI Ref ID J:48446)
- hematopoietic system phenotype
- increased leukocyte cell number (MGI Ref ID J:46182)
- increased eosinophil cell number (MGI Ref ID J:46182)
- increased differential percentage
- increased lymphocyte cell number (MGI Ref ID J:46182)
- increased monocyte cell number (MGI Ref ID J:46182)
- increased differential percentage
- increased neutrophil cell number (MGI Ref ID J:46182)
- immune system phenotype
- increased leukocyte cell number (MGI Ref ID J:46182)
- increased eosinophil cell number (MGI Ref ID J:46182)
- increased differential percentage
- increased lymphocyte cell number (MGI Ref ID J:46182)
- increased monocyte cell number (MGI Ref ID J:46182)
- increased differential percentage
- increased neutrophil cell number (MGI Ref ID J:46182)
- lung inflammation (MGI Ref ID J:48446)
- pneumonia arose between 1 and 4 months of life
- pancreas inflammation (MGI Ref ID J:48446)
- liver/biliary system phenotype
- abnormal bile duct morphology (MGI Ref ID J:48446)
- dilation of ducts adjacent to distended gall bladder
- abnormal gall bladder morphology (MGI Ref ID J:48446)
- distended
- muscle phenotype
- vascular smooth muscle cell hyperplasia (MGI Ref ID J:48446)
- renal/urinary system phenotype
- abnormal kidney morphology (MGI Ref ID J:48446)
- indistinct cortico-medullary junction
- reproductive system phenotype
- decreased litter size (MGI Ref ID J:46182)
- reduced fertility (MGI Ref ID J:46182)
- homozygous matings produced significantly fewer cumulative litters per breeding pair than wild-type matings
- respiratory system phenotype
- abnormal lung morphology (MGI Ref ID J:48446)
- proximal mucinous metaplasia
- lung hemorrhage (MGI Ref ID J:48446)
- into alveoli
- lung inflammation (MGI Ref ID J:48446)
- pneumonia arose between 1 and 4 months of life
- skeleton phenotype
- kyphosis (MGI Ref ID J:48446)
- lordosis (MGI Ref ID J:46182)
- apparent from birth
- skin/coat/nails phenotype
- abnormal dermal layer morphology (MGI Ref ID J:48446)
- lack of dermal matrix
- increased dermal vascular density
Research Applications
This mouse can be used to support research in many areas including:
Apoptosis Research
Endogenous Regulators
Extracellular Modulators
Cancer Research
Genes Regulating Growth and Proliferation
Cardiovascular Research
Ischemia studies
Vascular Defects
Cell Biology Research
Defects in Extracellular Matrix Molecules
Developmental Biology Research
Embryonic Lethality (Homozygous) (incomplete)
Internal/Organ Research
Lung Defects
Lymphoid Tissue Defects
Wound Healing
Research Tools
Apoptosis Research
Cancer Research
Cardiovascular Research
Hematological Research
Immunology and Inflammation Research
Internal/Organ Research
Sensorineural Research
Sensorineural Research
Eye Defects
| Allele Symbol | Thbs1tm1Hyn | ||
|---|---|---|---|
| Allele Name | targeted mutation 1, Richard O Hynes | ||
| Common Name(s) | TSP-1; TSP-1-; TSP1-; Thbs1-; Tsp-1KO; tbsp1-; | ||
| Mutation Made By | Jack Lawler, Beth Israel Deaconess Medical Center | ||
| Strain of Origin | 129S2/SvPas | ||
| ES Cell Line Name | D3 | ||
| ES Cell Line Strain | 129S2/SvPas | ||
| Gene Symbol and Name | Thbs1, thrombospondin 1 | ||
| Chromosome | 2 | ||
| Gene Common Name(s) | THBS; TSP; TSP-1; TSP1; Thbs-1; tbsp1; | ||
| Molecular Note | A neomycin selection cassette replaced exon 2, intron 3, and exon 3. An RNase protection assay demonstrated that no detectable transcript was present in multiple tissues of homozygous animals. Western analysis confirmed the absence of the encoded protein. [MGI Ref ID J:46182] | ||
Genotyping Protocols
Thbs1tm1Hyn, STD PCR, vers. 1
Helpful Links
Optimizing PCR Protocols
Lawler J; Sunday M; Thibert V; Duquette M; George EL; Rayburn H ; Hynes RO. 1998. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101(5):982-92. [PubMed: 9486968] [MGI Ref ID J:46182]
Thbs1tm1Hyn related
Abdelouahed M; Ludlow A; Brunner G; Lawler J. 2000. Activation of platelet-transforming growth factor beta-1 in the absence of thrombospondin-1. J Biol Chem 275(24):17933-6. [PubMed: 10849431] [MGI Ref ID J:62821]Agah A; Kyriakides TR; Lawler J; Bornstein P. 2002. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 161(3):831-9. [PubMed: 12213711] [MGI Ref ID J:78876]
Ali NA; Gaughan AA; Orosz CG; Baran CP; McMaken S; Wang Y; Eubank TD; Hunter M; Lichtenberger FJ; Flavahan NA; Lawler J; Marsh CB. 2008. Latency associated peptide has in vitro and in vivo immune effects independent of TGF-beta1. PLoS ONE 3(4):e1914. [PubMed: 18392110] [MGI Ref ID J:134350]
Bonnefoy A; Daenens K; Feys HB; De Vos R; Vandervoort P; Vermylen J; Lawler J; Hoylaerts MF. 2006. Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13. Blood 107(3):955-64. [PubMed: 16204318] [MGI Ref ID J:127571]
Budhani F; Leonard KA; Bergdahl A; Gao J; Lawler J; Davis EC. 2007. Vascular response to intra-arterial injury in the thrombospondin-1 null mouse. J Mol Cell Cardiol 43(2):210-4. [PubMed: 17583726] [MGI Ref ID J:123075]
Crawford SE; Stellmach V; Murphy-Ullrich JE; Ribeiro SM; Lawler J; Hynes RO; Boivin GP; Bouck N. 1998. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93(7):1159-70. [PubMed: 9657149] [MGI Ref ID J:48446]
Cursiefen C; Masli S; Ng TF; Dana MR; Bornstein P; Lawler J; Streilein JW. 2004. Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis. Invest Ophthalmol Vis Sci 45(4):1117-24. [PubMed: 15037577] [MGI Ref ID J:90088]
Daniel C; Schaub K; Amann K; Lawler J; Hugo C. 2007. Thrombospondin-1 is an endogenous activator of TGF-beta in experimental diabetic nephropathy in vivo. Diabetes 56(12):2982-9. [PubMed: 17878288] [MGI Ref ID J:132311]
Diamond AG; Gonterman RM; Anderson AL; Menon K; Offutt CD; Weaver CH; Philbrick WM; Foley J. 2006. Parathyroid Hormone Hormone-Related Protein and the PTH Receptor Regulate Angiogenesis of the Skin. J Invest Dermatol 126(9):2127-34. [PubMed: 16675960] [MGI Ref ID J:111733]
Frangogiannis NG; Ren G; Dewald O; Zymek P; Haudek S; Koerting A; Winkelmann K; Michael LH; Lawler J; Entman ML. 2005. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation 111(22):2935-42. [PubMed: 15927970] [MGI Ref ID J:112253]
Gutierrez LS; Suckow M; Lawler J; Ploplis VA; Castellino FJ. 2003. Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model. Carcinogenesis 24(2):199-207. [PubMed: 12584168] [MGI Ref ID J:79641]
Isenberg JS; Maxhimer JB; Hyodo F; Pendrak ML; Ridnour LA; DeGraff WG; Tsokos M; Wink DA; Roberts DD. 2008. Thrombospondin-1 and CD47 limit cell and tissue survival of radiation injury. Am J Pathol 173(4):1100-12. [PubMed: 18787106] [MGI Ref ID J:139652]
Isenberg JS; Ridnour LA; Perruccio EM; Espey MG; Wink DA; Roberts DD. 2005. Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A 102(37):13141-6. [PubMed: 16150726] [MGI Ref ID J:101420]
Isenberg JS; Romeo MJ; Abu-Asab M; Tsokos M; Oldenborg A; Pappan L; Wink DA; Frazier WA; Roberts DD. 2007. Increasing survival of ischemic tissue by targeting CD47. Circ Res 100(5):712-20. [PubMed: 17293482] [MGI Ref ID J:133700]
Isenberg JS; Romeo MJ; Yu C; Yu CK; Nghiem K; Monsale J; Rick ME; Wink DA; Frazier WA; Roberts DD. 2008. Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Blood 111(2):613-23. [PubMed: 17890448] [MGI Ref ID J:129994]
Keino H; Masli S; Sasaki S; Streilein JW; Stein-Streilein J. 2006. CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance. Invest Ophthalmol Vis Sci 47(4):1533-42. [PubMed: 16565389] [MGI Ref ID J:108447]
Kermorvant-Duchemin E; Sennlaub F; Sirinyan M; Brault S; Andelfinger G; Kooli A; Germain S; Ong H; d'Orleans-Juste P; Gobeil F; Zhu T; Boisvert C; Hardy P; Jain K; Falck JR; Balazy M; Chemtob S. 2005. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration. Nat Med 11(12):1339-45. [PubMed: 16311602] [MGI Ref ID J:104131]
Kopp HG; Hooper AT; Broekman MJ; Avecilla ST; Petit I; Luo M; Milde T; Ramos CA; Zhang F; Kopp T; Bornstein P; Jin DK; Marcus AJ; Rafii S. 2006. Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest 116(12):3277-91. [PubMed: 17143334] [MGI Ref ID J:117351]
Lawler J; Miao WM; Duquette M; Bouck N; Bronson RT; Hynes RO. 2001. Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice. Am J Pathol 159(5):1949-56. [PubMed: 11696456] [MGI Ref ID J:72391]
Lee NV; Sato M; Annis DS; Loo JA; Wu L; Mosher DF; Iruela-Arispe ML. 2006. ADAMTS1 mediates the release of antiangiogenic polypeptides from TSP1 and 2. EMBO J 25(22):5270-83. [PubMed: 17082774] [MGI Ref ID J:116155]
Ludlow A; Yee KO; Lipman R; Bronson R; Weinreb P; Huang X; Sheppard D; Lawler J. 2005. Characterization of integrin beta6 and thrombospondin-1 double-null mice. J Cell Mol Med 9(2):421-37. [PubMed: 15963261] [MGI Ref ID J:100142]
Masli S; Turpie B; Streilein JW. 2006. Thrombospondin orchestrates the tolerance-promoting properties of TGF{beta}-treated antigen-presenting cells. Int Immunol 18(5):689-99. [PubMed: 16569680] [MGI Ref ID J:108549]
Moura R; Tjwa M; Vandervoort P; Cludts K; Hoylaerts MF. 2007. Thrombospondin-1 activates medial smooth muscle cells and triggers neointima formation upon mouse carotid artery ligation. Arterioscler Thromb Vasc Biol 27(10):2163-9. [PubMed: 17761938] [MGI Ref ID J:135005]
Nishiwaki T; Yamaguchi T; Zhao C; Amano H; Hankenson KD; Bornstein P; Toyama Y; Matsuo K. 2006. Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing Fra1. J Bone Miner Res 21(4):596-604. [PubMed: 16598380] [MGI Ref ID J:128117]
Olerud J; Johansson M; Lawler J; Welsh N; Carlsson PO. 2008. Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets. Diabetes 57(7):1870-7. [PubMed: 18420490] [MGI Ref ID J:138228]
Otsuka G; Stempien-Otero A; Frutkin AD; Dichek DA. 2007. Mechanisms of TGF-beta1-induced intimal growth: plasminogen-independent activities of plasminogen activator inhibitor-1 and heterogeneous origin of intimal cells. Circ Res 100(9):1300-7. [PubMed: 17431190] [MGI Ref ID J:137777]
Pimanda JE; Ganderton T; Maekawa A; Yap CL; Lawler J; Kershaw G; Chesterman CN; Hogg PJ. 2004. Role of thrombospondin-1 in control of von Willebrand factor multimer size in mice. J Biol Chem 279(20):21439-48. [PubMed: 14981081] [MGI Ref ID J:89829]
Posey KL; Hankenson K; Veerisetty AC; Bornstein P; Lawler J; Hecht JT. 2008. Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen. Am J Pathol 172(6):1664-74. [PubMed: 18467703] [MGI Ref ID J:136242]
Rodriguez-Manzaneque JC; Lane TF; Ortega MA; Hynes RO; Lawler J; Iruela-Arispe ML. 2001. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 98(22):12485-90. [PubMed: 11606713] [MGI Ref ID J:72297]
Shaked Y; Bertolini F; Man S; Rogers MS; Cervi D; Foutz T; Rawn K; Voskas D; Dumont DJ; Ben-David Y; Lawler J; Henkin J; Huber J; Hicklin DJ; D'Amato RJ; Kerbel RS. 2005. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101-11. [PubMed: 15652753] [MGI Ref ID J:96033]
Sund M; Hamano Y; Sugimoto H; Sudhakar A; Soubasakos M; Yerramalla U; Benjamin LE; Lawler J; Kieran M; Shah A; Kalluri R. 2005. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors. Proc Natl Acad Sci U S A 102(8):2934-9. [PubMed: 15710885] [MGI Ref ID J:97878]
Thakar CV; Zahedi K; Revelo MP; Wang Z; Burnham CE; Barone S; Bevans S; Lentsch AB; Rabb H; Soleimani M. 2005. Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. J Clin Invest 115(12):3451-9. [PubMed: 16294224] [MGI Ref ID J:104708]
Voros G; Lijnen HR. 2006. Deficiency of thrombospondin-1 in mice does not affect adipose tissue development. J Thromb Haemost 4(1):277-8. [PubMed: 16409488] [MGI Ref ID J:135770]
Wang S; Wu Z; Sorenson CM; Lawler J; Sheibani N. 2003. Thrombospondin-1-deficient mice exhibit increased vascular density during retinal vascular development and are less sensitive to hyperoxia-mediated vessel obliteration. Dev Dyn 228(4):630-42. [PubMed: 14648840] [MGI Ref ID J:128776]
Wang Y; Wang S; Sheibani N. 2006. Enhanced proangiogenic signaling in thrombospondin-1-deficient retinal endothelial cells. Microvasc Res 71(3):143-51. [PubMed: 16624339] [MGI Ref ID J:112781]
Yano K; Brown LF; Lawler J; Miyakawa T; Detmar M. 2003. Thrombospondin-1 plays a critical role in the induction of hair follicle involution and vascular regression during the catagen phase. J Invest Dermatol 120(1):14-9. [PubMed: 12535193] [MGI Ref ID J:133248]
Yee KO; Connolly CM; Pines M; Lawler J. 2006. Halofuginone inhibits tumor growth in the polyoma middle T antigen mouse via a thrombospondin-1 independent mechanism. Cancer Biol Ther 5(2):218-24. [PubMed: 16418571] [MGI Ref ID J:110390]
Zamiri P; Masli S; Kitaichi N; Taylor AW; Streilein JW. 2005. Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci 46(3):908-19. [PubMed: 15728547] [MGI Ref ID J:105017]
Animal Health Reports
Room Number AX11
Colony Maintenance
Breeding & Husbandry When maintaining a live colony, these mice can be bred as homozygotes. Of note, homozygous matings result in fewer litters and an approximate 20% decrease in embryo/neonate viability. Diet Information LabDiet® 5K52/5K67
Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $155.60 Female or Male Homozygous for Thbs1tm1Hyn *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $311.20 Homozygous for Thbs1tm1Hyn x Homozygous for Thbs1tm1Hyn
| 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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Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $202.30 Female or Male Homozygous for Thbs1tm1Hyn *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $404.60 Homozygous for Thbs1tm1Hyn x Homozygous for Thbs1tm1Hyn
| 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. |
|---|---|
| Supply Notes |
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| Control | ||
|---|---|---|
| 000664 C57BL/6J | ||
| 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. | ||
For additional Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.
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