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 Congenic; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse   Donating Investigator Owen Witte,   University of California, Los Angeles

Description
These G protein-coupled receptor 4 targeted mutation mice are phenotypically normal in adulthood. Neonates show a higher frequency of mortality, however. Homozygous crosses produce litter sizes that are approximately 30% smaller than wild-type intercrosses on a C57BL/6 genetic background (backcross generations N3 and N5). A fraction of knockout embryos and neonates have spontaneous hemorrhages, as well as dilated and tortuous subcutaneous blood vessels. The mice show impaired association of vascular smooth muscle cells with capillaries and small arteries and veins. Mesangial cells in kidney glomeruli are significantly reduced in homozygous targeted mice. There is impaired contact between mesangial cells and renal glomerular capillaries. Some neonates exhibit respiratory distress with airway lining cell metaplasia. In studies of vascular pH sensing, microvessel outgrowth from homozygous aortas is less inhibited by acidic extracellular pH. Although an IRES-GFP insertion was incorporated in this strain, it can not be reliably observed through microscopy. This strain may be useful in studies of vascular development and G protein receptor function.

Development
The open reading frame of the gene was replaced with IRES-GFP and a PGK-neomycin resistance cassette. The targeting vector was introduced to 129X1/SvJ-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient C57BL/6J blastocysts, and then backcrossed to the same for more than 6 generations.

Control Information

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

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Gpr4^tm1Witt/Gpr4^tm1Witt

        either: B6.129X1-Gpr4^tm1Witt or (involves: 129X1/SvJ * C57BL/6)

• mortality/aging
• partial neonatal lethality
  • at 1 day after birth litter sizes from homozygous crosses are smaller; however, crosses of homozygotes to wild-type mice produce normal sized litters   (MGI Ref ID J:118276)
  • some neonates develop severe respiratory distress and die shortly after birth   (MGI Ref ID J:118276)
• partial postnatal lethality
  • in mice backcrossed for 5 generations to C57BL/6 the frequency of homozygotes is reduced to 16.8% by 2 weeks after birth rather than the expected 25%   (MGI Ref ID J:118276)
  • mice (backcrossed for 5 generations to C57BL/6) that die usually die within 2 weeks with most lost in the first 2 days   (MGI Ref ID J:118276)
• cardiovascular system phenotype
• abnormal blood vessel morphology
  • dilated, tortuous, and poorly organized blood vessels are found in neonatal skin   (MGI Ref ID J:118276)
• • abnormal angiogenesis
    • microvessel outgrowth from cultured aortic rings is not suppressed at pH 6.9 unlike in aortic rings from wild-type controls   (MGI Ref ID J:118276)
    • however, microvessel outgrowth at pH 7.5 is similar to controls   (MGI Ref ID J:118276)
  • abnormal vascular smooth muscle morphology
    • dilated small arteries and veins are poorly enveloped by smooth muscle cells   (MGI Ref ID J:118276)
    • however, smooth muscle cell coverage of large vessels is similar to wild-type controls   (MGI Ref ID J:118276)
• hemorrhage
  • macroscopic superficial hemorrhages in the limbs, head and regions of the body wall are found in 11 of 66 embryos   (MGI Ref ID J:118276)
  • however, bleeding times and platelet numbers are similar to wild-type controls   (MGI Ref ID J:118276)
• • hemoperitoneum
    • seen in mice that die perinatally   (MGI Ref ID J:118276)
  • kidney hemorrhage
    • hemorrhages in the glomeruli and parenchyma of the kidney are seen in some neonates   (MGI Ref ID J:118276)
  • • glomerulus hemorrhage
      • glomerular hemorrhage is seen in some neonates   (MGI Ref ID J:118276)
  • lung hemorrhage
    • hemorrhages in the parenchyma of the lung are seen in some neonates   (MGI Ref ID J:118276)
  • petechiae
    • petechial hemorrhages are seen along blood vessel tracks in the skin   (MGI Ref ID J:118276)
• renal/urinary system phenotype
• abnormal renal glomerulus morphology
  • defect in the close contact between mesangial cells and glomerular capillaries   (MGI Ref ID J:118276)
• • mesangial cell hypoplasia
    • fewer mesangial cells are present in most glomeruli   (MGI Ref ID J:118276)
• kidney hemorrhage
  • hemorrhages in the glomeruli and parenchyma of the kidney are seen in some neonates   (MGI Ref ID J:118276)
• • glomerulus hemorrhage
    • glomerular hemorrhage is seen in some neonates   (MGI Ref ID J:118276)
• respiratory system phenotype
• bronchial epithelial hyperplasia
  • neonates displaying respiratory distress have regions of the bronchiolar epithelium with abnormal cells that have enlarged clear cytoplasm and form multiple cell layers   (MGI Ref ID J:118276)
  • this airway lining metaplasia extends peripherally to respiratory and terminal bronchioles and varies in severity   (MGI Ref ID J:118276)
  • these abnormal cells are not detected in surviving mice   (MGI Ref ID J:118276)
• lung hemorrhage
  • hemorrhages in the parenchyma of the lung are seen in some neonates   (MGI Ref ID J:118276)
• respiratory distress
  • severe respiratory distress is seen in some neonates   (MGI Ref ID J:118276)
• homeostasis/metabolism phenotype
• cyanosis
  • neonates with difficulty breathing become cyanotic   (MGI Ref ID J:118276)
• muscle phenotype
• abnormal vascular smooth muscle morphology
  • dilated small arteries and veins are poorly enveloped by smooth muscle cells   (MGI Ref ID J:118276)
  • however, smooth muscle cell coverage of large vessels is similar to wild-type controls   (MGI Ref ID J:118276)
• integument phenotype
• petechiae
  • petechial hemorrhages are seen along blood vessel tracks in the skin   (MGI Ref ID J:118276)

View Research Applications

Research Applications

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

Developmental Biology Research
Internal/Organ Defects
      kidney
      kidney: vasculature
      lung
      vasculature
Perinatal Lethality
      Homozygous

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Gpr4tm1Witt
Allele Name		targeted mutation 1, Owen N Witte
Allele Type		Targeted (knock-out)
Common Name(s)		Gpr4-;
Mutation Made By		Owen Witte,   University of California, Los Angeles
Strain of Origin		129X1/SvJ
ES Cell Line Strain		129
Gene Symbol and Name		Gpr4, G protein-coupled receptor 4
Chromosome		7
Molecular Note		The coding region was replaced by the IRES-GFP and PGK-neo cassette. Absence of transcript was confirmed by RT-PCR. [MGI Ref ID J:118276]

Genotyping

Genotyping Information

Genotyping Protocols

Gpr4^tm1Witt, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Yang LV; Radu CG; Roy M; Lee S; McLaughlin J; Teitell MA; Iruela-Arispe ML; Witte ON. 2007. Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol 27(4):1334-47. [PubMed: 17145776]  [MGI Ref ID J:118276]

Additional References

Gpr4^tm1Witt related

Sun X; Yang LV; Tiegs BC; Arend LJ; McGraw DW; Penn RB; Petrovic S. 2010. Deletion of the pH sensor GPR4 decreases renal acid excretion. J Am Soc Nephrol 21(10):1745-55. [PubMed: 20798260]  [MGI Ref ID J:185906]

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	When maintained as a live colony, heterozygotes or homozygotes may be bred. Homozygous crosses produce litters that are notably smaller than wildtype crosses due to perinatal lethality.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

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

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