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

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Gustav E. Lienhard,   Dartmouth Medical School

Description
Mice homozygous for the Irs4^tm1Lhd targeted mutation are viable and fertile. However, homozygous mutant mice do appear to be at a greater risk of perinatal lethality and tend to produce fewer litters. At birth, surviving mice appear normal in size and do not display any gross physical or behavioral abnormalities. RT-PCR fails to detect Irs4 mRNA in any tissues analyzed. Growth rate appears to be slightly retarded beginning 6 weeks of age (males about 10% lighter). Homozygotes also exhibit impaired glucose tolerance, and have slightly lower blood glucose levels when compared to wildtype mice. These phenotypes are more pronounced in males than in females.

Development
A targeting vector containing a herpes simplex virus thymidine kinase gene and a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt the single Irs4 exon. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric male mice were bred to C57BL/6 females. Offspring animals were bred to homozygosity.

Control Information

	Control
	101045 B6129SF2/J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Irs4^tm1Lhd/Irs4^tm1Lhd

        involves: 129S4/SvJae * C57BL/6

• reproductive system phenotype
• abnormal fertility/fecundity
  • female homozygotes exhibit reduced ability to produce live offspring when mated with hemizygous mutant males   (MGI Ref ID J:59964)
• • decreased litter size
    • pairs of mutant mice produce an average of 1.8 ± 0.4 litters per pair (range 0-3 litters) over a 3-month period, whereas wild-type mice produce an average of 2.9 ± 0.1 litters per pair (range 2-3 litters)   (MGI Ref ID J:59964)
    • 36% of mutant litters die within a few days of birth relative to only 5% of wild-type litters   (MGI Ref ID J:59964)
    • the average size of surviving litters from mutant mice is slightly reduced relative to wild-type litters   (MGI Ref ID J:59964)
• behavior/neurological phenotype
• abnormal maternal nurturing
  • female homozygotes may be less nurturing of their pups than wild-type females, as suggested by an observed decrease in the number of surviving litters   (MGI Ref ID J:59964)
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • female homozygotes show slightly reduced blood glucose levels in both the fasted and fed states at 6-10 weeks, and in the fed state at 6 months; however, none of these differences reach statistical significance   (MGI Ref ID J:59964)
  • in addition, plasma insulin levels remain unaffected in the fed and fasted state at both ages   (MGI Ref ID J:59964)
• • abnormal glucose tolerance
    • at 6 months, older female homozygotes exhibit only a very slightly impaired glucose tolerance, which is statistically significant at 10 min but not at other time points   (MGI Ref ID J:59964)
• growth/size phenotype
• *normal* growth/size phenotype
  • female homozygotes exhibit a very slight reduction in body size relative to wild-type mice; however, this difference does not reach statistical significance   (MGI Ref ID J:59964)

Irs4^tm1Lhd/Y

        involves: 129S4/SvJae * C57BL/6

• homeostasis/metabolism phenotype
• decreased circulating glucose level
  • at 6-10 weeks, male hemizygotes exhibit a slight but significant reduction in blood glucose levels in both the fasted and fed states; however, these differences become statistically insignificant at 6 months   (MGI Ref ID J:59964)
  • in contrast, plasma insulin levels remain unaffected in the fed and fasted state at both ages   (MGI Ref ID J:59964)
• impaired glucose tolerance
  • at 6-10 weeks, male hemizygotes show a slightly impaired glucose tolerance, with significant differences noted at the 90 and 120 min time points   (MGI Ref ID J:59964)
  • at 6 months, significant differences are only noted at the 20 min point of the oral glucose tolerance test   (MGI Ref ID J:59964)
• reproductive system phenotype
• abnormal fertility/fecundity
  • male hemizygotes exhibit reduced ability to produce live offspring when mated with homozygous mutant females   (MGI Ref ID J:59964)
• • decreased litter size
    • pairs of mutant mice produce an average of 1.8 ± 0.4 litters per pair (range 0-3 litters) over a 3-month period, whereas wild-type mice produce an average of 2.9 ± 0.1 litters per pair (range 2-3 litters)   (MGI Ref ID J:59964)
    • 36% of mutant litters die within a few days of birth relative to only 5% of wild-type litters   (MGI Ref ID J:59964)
    • the average size of surviving litters from mutant mice is slightly reduced relative to wild-type litters   (MGI Ref ID J:59964)
• growth/size phenotype
• decreased body weight
  • at 9 weeks and beyond, the weight of male hemizygotes is ~10% less that of wild-type mice   (MGI Ref ID J:59964)
• postnatal growth retardation
  • male hemizygotes exhibit a growth retardation beyond 6 weeks of age   (MGI Ref ID J:59964)

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

Irs4^tm1Lhd/Irs4^tm1Lhd

        involves: 129S4/SvJae * BALB/c

• reproductive system phenotype
• abnormal fertility/fecundity
  • female homozygotes exhibit reduced ability to produce live offspring when mated with hemizygous mutant males   (MGI Ref ID J:59964)
• • decreased litter size
    • pairs of mutant mice produce an average of 2.0 ± 0.5 litters per pair (range 0-3), whereas wild-type mice produce an average of 3.1 ± 0.1 litters per pair (range 3-4)   (MGI Ref ID J:59964)
    • ~50% of mutant litters die within a few days of birth relative to only 8% of wild-type litters   (MGI Ref ID J:59964)
    • the average sizes of surviving litters are almost the same for mutant and wild-type mice   (MGI Ref ID J:59964)

Irs4^tm1Lhd/Y

        involves: 129S4/SvJae * BALB/c

• homeostasis/metabolism phenotype
• impaired glucose tolerance
  • at 6-10 weeks, male hemizygotes show an impaired tolerance that is statistically significant at the 60, 90, and 120 min time points of the oral glucose tolerance test   (MGI Ref ID J:59964)
• reproductive system phenotype
• abnormal fertility/fecundity
  • male hemizygotes exhibit reduced ability to produce live offspring when mated with homozygous mutant females   (MGI Ref ID J:59964)
• • decreased litter size
    • pairs of mutant mice produce an average of 2.0 ± 0.5 litters per pair (range 0-3), whereas wild-type mice produce an average of 3.1 ± 0.1 litters per pair (range 3-4)   (MGI Ref ID J:59964)
    • ~50% of mutant litters die within a few days of birth relative to only 8% of wild-type litters   (MGI Ref ID J:59964)
    • the average sizes of surviving litters are almost the same for mutant and wild-type mice   (MGI Ref ID J:59964)

View Research Applications

Research Applications

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

Irs4^tm1Lhd related

Diabetes and Obesity Research
Insulin Receptors and Growth Factors

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Irs4tm1Lhd
Allele Name		targeted mutation 1, Gustav E Lienhard
Allele Type		Targeted (knock-out)
Common Name(s)		IRS-4 null; Irs4-;
Mutation Made By		Gustav Lienhard,   Dartmouth Medical School
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Irs4, insulin receptor substrate 4
Chromosome		X
Gene Common Name(s)		IRS-4; PY160;
Molecular Note		A neomycin resistance cassette replaced the entire coding sequence of the gene except for 457 bp at the 3' end. Reverse transcription-PCR detected no mRNA expression in brain, skeletal muscle, kidney, or liver of homozygous mutant mice. [MGI Ref ID J:59964]

Genotyping

Genotyping Information

Genotyping Protocols

Irs4^{tm1 Lhd}, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Fantin VR; Wang Q; Lienhard GE; Keller SR. 2000. Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab 278(1):E127-33. [PubMed: 10644546]  [MGI Ref ID J:59964]

Additional References

Laustsen PG; Michael MD; Crute BE; Cohen SE; Ueki K; Kulkarni RN; Keller SR; Lienhard GE; Kahn CR. 2002. Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes Dev 16(24):3213-22. [PubMed: 12502742]  [MGI Ref ID J:80976]

Irs4^tm1Lhd related

Laustsen PG; Michael MD; Crute BE; Cohen SE; Ueki K; Kulkarni RN; Keller SR; Lienhard GE; Kahn CR. 2002. Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes Dev 16(24):3213-22. [PubMed: 12502742]  [MGI Ref ID J:80976]

Xu X; Coats JK; Yang CF; Wang A; Ahmed OM; Alvarado M; Izumi T; Shah NM. 2012. Modular genetic control of sexually dimorphic behaviors. Cell 148(3):596-607. [PubMed: 22304924]  [MGI Ref ID J:181334]

Health & husbandry

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.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & Husbandry	This strain arose on a B6;129 background and is maintained on the same. Coat color expected from breeding:Black.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	101045 B6129SF2/J
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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