Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation N5p   Donating Investigator Nancy Speck,   Dartmouth Medical School

Description
Heterozygous mice are viable, fertile, devoid of hemorrhagic lesions, and exhibit mild hematopoietic impairment. Mice that are homozygous for the targeted mutation have an embryonic lethal phenotype; animals are alive at embryonic day 11.5, but start dying at embryonic day 12.5. Embryos exhibit extensive hemorrhagic lesions in the central nervous system including the intraventricular regions and metencephalon as well as segmental bleeds at the VII-VIII cranial nerve complex, cervical, thoracic, and caudal regions. At embryonic day 10.5, symmetrical and bilateral necrosis preceding hemorrhage is observed in homozygotes. Homozygous disruption of the endogenous gene completely blocks definitive erythropoiesis, myelopoiesis, and lymphopoiesis. This mutant may be useful in leukemia studies as disruption of the human homolog of this gene is associated with many different leukemias.

Development
A targeting vector containing a phosphoglycerol kinase-driven neomycin resistance gene disrupted the 3.2 kb region coding for amino acids 143-178 (the final 35 amino acids in the DNA binding domain) of the endogenous gene. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were backcrossed to C57BL/6J females. Heterozygotes were backcrossed to (129S1/SvImJ x C57BL/6J)F1 mice for more than 10 generations and then backcrossed to C57BL/6J for at least five more generations.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Runx1^tm1Spe/Runx1⁺

        either: (involves: 129S4/SvJae * BALB/c * C57BL/6 * CBA/Ca) or (involves: 129S4/SvJae * C57BL/6 * CBA/Ca)

• tumorigenesis
• T cell derived lymphoma (MGI Ref ID J:80829)
  • survival of mutants shows slight but significant increase compared to transgenic mice on a wild-type Runx1 background

Runx1^tm1Spe/Runx1⁺

        either: (involves: 129S4/SvJae * BALB/c) or (involves: 129S4/SvJae * C57BL/6)

• tumorigenesis
• *normal* tumorigenesis (MGI Ref ID J:80829)
  • mice infected with Moloney murine leukemia virus within 24 hours of birth do not show any increase in tumor incidence or latency compared to infected littermate controls
• embryogenesis phenotype
• abnormal embryonic hematopoiesis (MGI Ref ID J:120100)
  • at E11.5, animals have a >3-fold decrease in CFU-C in AGM (aorta/gonad/mesonephros) regions than wild-type embryos in the AGM region
• hematopoietic system phenotype
• abnormal embryonic hematopoiesis (MGI Ref ID J:120100)
  • at E11.5, animals have a >3-fold decrease in CFU-C in AGM (aorta/gonad/mesonephros) regions than wild-type embryos in the AGM region
• decreased CD4-positive T cell number (MGI Ref ID J:120100)
  • a significant decrease in percentage of CD4+ splenic T cells and in the CD4+:CD8+ ratio is observed compared to wild-type adults, but percentage of CD8+ T cells is not changed
• immune system phenotype
• decreased CD4-positive T cell number (MGI Ref ID J:120100)
  • a significant decrease in percentage of CD4+ splenic T cells and in the CD4+:CD8+ ratio is observed compared to wild-type adults, but percentage of CD8+ T cells is not changed

Runx1^tm1Spe/Runx1^tm1Spe

        either: (involves: 129S4/Jae * BALB/c) or (involves: 129S4/SvJae * C57BL/6)

• lethality-prenatal/perinatal
• embryonic lethality during organogenesis (MGI Ref ID J:35115)
  • die between E11.5 and E12.5
• cardiovascular system phenotype
• hemorrhage (MGI Ref ID J:35115)
  • extensive hemorrhages, with 14% of homozygotes showing hemorrhaging at E10.5, 73% at E11.5 and 100% at E12.5
• internal hemorrhage (MGI Ref ID J:35115)
  • most extensive hemorrhages involve the central nervous system and are located in the isthmus, ventral metencephalon, and spinal cord
  • focal petechial hemorrhages are seen in peripheral nerves and intersegmental regions, especially prominent at the nerve roots of VII-VIII cranial nerve complex and at some spinal nerves
  • mesodermal petechial hemorrhages are seen in a small number of embryos
• hemopericardium (MGI Ref ID J:35115)
  • pericardiac and peritoneal hemorrhages are seen in some embryos
• hematopoietic system phenotype
• abnormal erythropoiesis (MGI Ref ID J:35115)
  • only primitive nucleated erythroid cells are seen in liver sections or smears at E11 and E12.5, respectively, indicating a block in definitive erythropoiesis
  • no erythroid colonies differentiate from yolk sac cells as in wild-type
• impaired hematopoiesis (MGI Ref ID J:35115)
  • fetal liver hematopoiesis is impaired, however primitive erythrocytes are normal
• impaired myelopoiesis (MGI Ref ID J:35115)
  • no myeloid colonies differentiate from yolk sac cells as in wild-type
• cellular phenotype
• necrosis (MGI Ref ID J:35115)
  • foci of cellular necrosis, often bilateral and symmetrical, are seen at the nerve/CNS interfaces of cranial and spinal nerves at E10.5
  • somitic/intersomitic necrosis is seen in the lower thoracic and lumbar regions
• immune system phenotype
• impaired myelopoiesis (MGI Ref ID J:35115)
  • no myeloid colonies differentiate from yolk sac cells as in wild-type

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cardiovascular Research
Vascular Defects (defective leukocyte function)

Developmental Biology Research
Embryonic Lethality (Homozygous)
Internal/Organ Defects (hematopoietic defects)
Lymphoid Tissue Defects (hematopoietic defects)

Hematological Research
Hematopoietic Defects
Immunological Defects

Immunology and Inflammation Research
Lymphoid Tissue Defects (hematopoietic development)

Internal/Organ Research
Liver Defects

Research Tools
Cancer Research (Leukemia)
Hematological Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Runx1tm1Spe
Allele Name		targeted mutation 1, Nancy A Speck
Allele Type		Targeted (knock-out)
Common Name(s)		Cbfa2-; Cbfa2rd; Runx1-; Runx1deltaE4; Runx1rd;
Mutation Made By		Nancy Speck,   Dartmouth Medical School
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Runx1, runt related transcription factor 1
Chromosome		16
Gene Common Name(s)		AI462102; AML1; AML1-EVI-1; AMLCR1; CBFA2; Cbfa2; EVI-1; PEBP2aB; Pebp2a2; core binding factor alpha 2; expressed sequence AI462102; runt domain, alpha subunit 2;
Molecular Note		Exon 4, which encodes a portion of the DNA-binding domain, was deleted by the insertion of a PGK-neo cassette. RT-PCR analysis showed a lack of normal transcript in homozygous mutant mice. [MGI Ref ID J:35115]

Genotyping

Genotyping Information

Genotyping Protocols

Runx1^tm1Spe, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Wang Q; Stacy T; Binder M; Marin-Padilla M; Sharpe AH; Speck NA. 1996. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci U S A 93(8):3444-9. [PubMed: 8622955]  [MGI Ref ID J:35115]

Additional References

Runx1^tm1Spe related

Kundu M; Compton S; Garrett-Beal L; Stacy T; Starost MF; Eckhaus M; Speck NA; Liu PP. 2005. Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma. Blood 106(10):3621-4. [PubMed: 16051740]  [MGI Ref ID J:106809]

Matheny CJ; Speck ME; Cushing PR; Zhou Y; Corpora T; Regan M; Newman M; Roudaia L; Speck CL; Gu TL; Griffey SM; Bushweller JH; Speck NA. 2007. Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. EMBO J 26(4):1163-75. [PubMed: 17290219]  [MGI Ref ID J:120100]

North T; Gu TL; Stacy T; Wang Q; Howard L; Binder M; Marin-Padilla M; Speck NA. 1999. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126(11):2563-75. [PubMed: 10226014]  [MGI Ref ID J:56184]

Theriault FM; Nuthall HN; Dong Z; Lo R; Barnabe-Heider F; Miller FD; Stifani S. 2005. Role for Runx1 in the proliferation and neuronal differentiation of selected progenitor cells in the mammalian nervous system. J Neurosci 25(8):2050-61. [PubMed: 15728845]  [MGI Ref ID J:97371]

Vaillant F; Blyth K; Andrew L; Neil JC; Cameron ER. 2002. Enforced Expression of Runx2 Perturbs T Cell Development at a Stage Coincident with beta-Selection. J Immunol 169(6):2866-74. [PubMed: 12218099]  [MGI Ref ID J:79075]

Woolf E; Xiao C; Fainaru O; Lotem J; Rosen D; Negreanu V; Bernstein Y; Goldenberg D; Brenner O; Berke G; Levanon D; Groner Y. 2003. Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc Natl Acad Sci U S A 100(13):7731-6. [PubMed: 12796513]  [MGI Ref ID J:84629]

Wotton S; Stewart M; Blyth K; Vaillant F; Kilbey A; Neil JC; Cameron ER. 2002. Proviral Insertion Indicates a Dominant Oncogenic Role for Runx1/AML-1 in T-Cell Lymphoma. Cancer Res 62(24):7181-5. [PubMed: 12499254]  [MGI Ref ID J:80829]

Zeigler BM; Sugiyama D; Chen M; Guo Y; Downs KM; Speck NA. 2006. The allantois and chorion, when isolated before circulation or chorio-allantoic fusion, have hematopoietic potential. Development 133(21):4183-92. [PubMed: 17038514]  [MGI Ref ID J:114096]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are maintained as heterozygotes. Homozygotes are embryonic lethal.
Mating System	+/+ sibling x Heterozygote         (Female x Male)

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	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.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

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.

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Ordering and Purchasing Information

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Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

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