Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   22-MAY-13 Species laboratory mouse Generation N9pN1+F1 (11-MAR-13) Generation Definitions   Donating Investigator Charles O'Brien,   University of Arkansas for Medical Scien

Description
These RANKL^f/f mutant mice possess loxP sites flanking exons 3-4 of the tumor necrosis factor (ligand) superfamily, member 11 (Tnfsf11) gene. Tnfsf11 encodes the cytokine RANKL, a ligand for RANK, both of which are essential for osteoclast differentiation, development, function and survival. RANKL is expressed in chondrocytes and osteocytes embedded in the bone matrix where it controls mineralized cartilage resorption, bone remodeling, and bone loss. Mice that are homozygous for this allele are viable and fertile. When these mutant mice are bred to mice that express Cre recombinase, resulting offspring will have exons 3-4 deleted in the cre-expressing tissue(s).

For example, when bred to B6.Cg-Tg(Prrx1-cre)1Cjt/J mice (Stock No. 005584) expressing Cre recombinase in the developing limbs and parts of the skull, double mutant mice had increased bone mineral density and cancellous bone volume.

When bred to B6.Cg-Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/J mice (Stock No. 006361) expressing Cre recombinase under the control of the tetracycline analog doxycycline, EGFP-Cre fusion protein expression is restricted to the osteoblast lineage. In the absence of doxycycline, Cre expression results in altered bone mineral density, bone volume and cartilage.

When bred to a strain carrying Tg(BGLAP-cre)1Clem (Stock No. 019509), Cre recombinase expression in osteoblasts results in increased bone mineral density, increased trabecular volume, and abnormal cartilage.

Development
A targeting vector was designed to insert a frt-flanked PGK-neo cassette followed by a loxP site upstream of exon 3, and a second loxP site just downstream of exon 4 of the tumor necrosis factor (ligand) superfamily, member 11 (Tnfsf11) gene. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric males were bred to C57BL/6 females. Offspring were bred with 129S4/SvJaeSor-Gt(ROSA)26Sor^tm1(FLP1)Dym/J mice (Stock No. 003946) to delete the neo cassette, and progeny were crossed to remove the Flp-expressing transgene. The resulting homozygous RANKLf/f mice were backcrossed to C57BL/6 mice for at least 9 generations. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation.

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Osteopetrosis, Autosomal Recessive 2; OPTB2   (TNFSF11)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Tnfsf11^tm1.1Caob/Tnfsf11^tm1.1Caob Tg(BGLAP-cre)1Clem/0

        involves: 129S * 129X1/SvJ * C57BL/6 * FVB/NJ   (conditional)

• skeleton phenotype
• abnormal cartilage morphology
  • mice exhibit unresorbed cartilage unlike wild-type mice   (MGI Ref ID J:177558)
• • increased long bone epiphyseal plate size
    • widened growth plate in the femur   (MGI Ref ID J:177558)
• increased bone mineral density
  • at 5 weeks of age   (MGI Ref ID J:177558)
• increased trabecular bone volume
  • at 5 weeks of age   (MGI Ref ID J:177558)
• craniofacial phenotype
• failure of tooth eruption
  • in some mice   (MGI Ref ID J:177558)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Tnfsf11^tm1.1Caob/Tnfsf11^tm1.1Caob Tg(Prrx1-cre)1Cjt/0

        involves: 129S1/Sv * 129S4/SvJaeSor * 129X1/SvJ * C57BL/6   (conditional)

• skeleton phenotype
• *normal* skeleton phenotype
  • mice exhibit normal bone mass and tooth eruption   (MGI Ref ID J:177558)
• • abnormal cartilage morphology
    • mice exhibit unresorbed cartilage unlike wild-type mice   (MGI Ref ID J:177558)
  • • increased long bone epiphyseal plate size
      • widened growth plate in the femur   (MGI Ref ID J:177558)
  • decreased osteoclast cell number
    • absent in femur   (MGI Ref ID J:177558)
  • increased bone mineral density   (MGI Ref ID J:177558)
  • increased trabecular bone volume
    • in the femur but not the spine   (MGI Ref ID J:177558)
  • osteopetrosis
    • severe   (MGI Ref ID J:177558)
• immune system phenotype
• decreased osteoclast cell number
  • absent in femur   (MGI Ref ID J:177558)
• hematopoietic system phenotype
• decreased osteoclast cell number
  • absent in femur   (MGI Ref ID J:177558)

Tnfsf11^tm1.1Caob/Tnfsf11^tm1.1Caob Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/0

        involves: 129S * 129X1/SvJ * C57BL/6 * CD-1   (conditional)

• skeleton phenotype
• *normal* skeleton phenotype
  • mice treated with doxycycline until 4 months of age exhibit normal cancellous architecture at 6 months   (MGI Ref ID J:177558)
• • abnormal cartilage morphology
    • mice exhibit unresorbed cartilage unlike wild-type mice   (MGI Ref ID J:177558)
  • • increased long bone epiphyseal plate size
      • widened growth plate in the femur   (MGI Ref ID J:177558)
  • increased bone mineral density
    • at 5 weeks of age   (MGI Ref ID J:177558)
  • increased trabecular bone volume
    • at 5 weeks of age   (MGI Ref ID J:177558)
• craniofacial phenotype
• failure of tooth eruption
  • in all mice   (MGI Ref ID J:177558)
  • however, exposure to doxycycline restores tooth eruption   (MGI Ref ID J:177558)

View Research Applications

Research Applications

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

Developmental Biology Research
Skeletal Defects
      osteopetrosis

Internal/Organ Research
Skeleton
      Bone

Research Tools
Cre-lox System
      loxP-flanked Sequences
Developmental Biology Research
      Cre-lox System

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Tnfsf11tm1.1Caob
Allele Name		targeted mutation 1.1, Charles O'Brien
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		RANKLf;
Mutation Made By		Charles O'Brien,   University of Arkansas for Medical Scien
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Tnfsf11, tumor necrosis factor (ligand) superfamily, member 11
Chromosome		14
Gene Common Name(s)		CD254; Ly109l; ODF; OPGL; OPTB2; RANKL; TNF-related activation-induced cytokine; TRANCE; Trance; hRANKL2; osteoclast differentiation factor; sOdf;
Molecular Note		An FRT-flanked neo cassette with a 5' loxP site was inserted upstream of exon 3. An additional loxP site was inserted downstream of exon 4. Flp-mediated recombination removed the neo cassette and left exons 3 and 4 floxed. [MGI Ref ID J:177558]

Genotyping

Genotyping Information

Genotyping Protocols

Tnfsf11^tm1.1Caob, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Xiong J; Onal M; Jilka RL; Weinstein RS; Manolagas SC; O'Brien CA. 2011. Matrix-embedded cells control osteoclast formation. Nat Med 17(10):1235-41. [PubMed: 21909103]  [MGI Ref ID J:177558]

Additional References

Tnfsf11^tm1.1Caob related

Onal M; Xiong J; Chen X; Thostenson JD; Almeida M; Manolagas SC; O'Brien CA. 2012. Receptor activator of nuclear factor kappaB ligand (RANKL) protein expression by B lymphocytes contributes to ovariectomy-induced bone loss. J Biol Chem 287(35):29851-60. [PubMed: 22782898]  [MGI Ref ID J:190415]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB29

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred together.
Mating System	Homozygote x Homozygote         (Female x Male)   22-MAY-13

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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