Overview

These G protein-coupled receptor 4 targeted mutation mice are phenotypically normal in adulthood. Neonates show a higher frequency of mortality, however. 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. In studies of vascular pH sensing, microvessel outgrowth from homozygous aortas is less inhibited by acidic extracellular pH. This strain may be useful in studies of vascular development and G protein receptor function.

Donating Investigator

Owen Witte, University of California, Los Angeles

Genetic overview

Genetic Background	Generation

Gpr4^tm1Witt

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Gpr4	G protein-coupled receptor 4

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Research Applications

Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed 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 Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

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):1334-47PubMed: 17145776 MGI: J:118276

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Genetics

Gpr4^tm1Witt

Allele Symbol: Gpr4^tm1Witt

Allele Name	targeted mutation 1, Owen N Witte
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Gpr4^-
Gene Symbol and Name	Gpr4, G protein-coupled receptor 4
Gene Synonym(s)
Strain of Origin	129X1/SvJ
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.
Mutations Made By	Owen Witte, University of California, Los Angeles

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

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

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

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

cardiovascular system phenotype

abnormal angiogenesis
- Normal - however, microvessel outgrowth at pH 7.5 is similar to controls
- microvessel outgrowth from cultured aortic rings is not suppressed at pH 6.9 unlike in aortic rings from wild-type controls

abnormal blood vessel morphology
- dilated, tortuous, and poorly organized blood vessels are found in neonatal skin

abnormal vascular smooth muscle morphology
- dilated small arteries and veins are poorly enveloped by smooth muscle cells
- Normal - however, smooth muscle cell coverage of large vessels is similar to wild-type controls

glomerulus hemorrhage
- glomerular hemorrhage is seen in some neonates

hemoperitoneum
- seen in mice that die perinatally

hemorrhage
- Normal - however, bleeding times and platelet numbers are similar to wild-type controls
- macroscopic superficial hemorrhages in the limbs, head and regions of the body wall are found in 11 of 66 embryos

kidney hemorrhage
- hemorrhages in the glomeruli and parenchyma of the kidney are seen in some neonates

lung hemorrhage
- hemorrhages in the parenchyma of the lung are seen in some neonates

homeostasis/metabolism phenotype

cyanosis
- neonates with difficulty breathing become cyanotic

integument phenotype

petechiae
- petechial hemorrhages are seen along blood vessel tracks in the skin

mortality/aging

neonatal lethality, incomplete penetrance
- at 1 day after birth litter sizes from homozygous crosses are smaller; however, crosses of homozygotes to wild-type mice produce normal sized litters
- some neonates develop severe respiratory distress and die shortly after birth

postnatal lethality, incomplete penetrance
- 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%
- mice (backcrossed for 5 generations to C57BL/6) that die usually die within 2 weeks with most lost in the first 2 days

muscle phenotype

abnormal vascular smooth muscle morphology
- dilated small arteries and veins are poorly enveloped by smooth muscle cells
- Normal - however, smooth muscle cell coverage of large vessels is similar to wild-type controls

renal/urinary system phenotype

abnormal renal glomerulus morphology
- defect in the close contact between mesangial cells and glomerular capillaries

glomerulus hemorrhage
- glomerular hemorrhage is seen in some neonates

kidney hemorrhage
- hemorrhages in the glomeruli and parenchyma of the kidney are seen in some neonates

mesangial cell hypoplasia
- fewer mesangial cells are present in most glomeruli

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
- Normal - these abnormal cells are not detected in surviving mice
- this airway lining metaplasia extends peripherally to respiratory and terminal bronchioles and varies in severity

lung hemorrhage
- hemorrhages in the parenchyma of the lung are seen in some neonates

respiratory distress
- severe respiratory distress is seen in some neonates

References

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):1334-47PubMed: 17145776 MGI: J:118276

Additional - Gpr4^tm1Witt related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Gpr4
- Genotyping resources and troubleshooting
Breeding Considerations

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.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129X1-Gpr4^tm1Witt/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008580 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous for Gpr4<tm1Witt>

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Gpr4tm1Witt

Allele Symbol: Gpr4tm1Witt

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Gpr4tm1Witt/Gpr4tm1Witteither: B6.129X1-Gpr4 or (involves: 129X1/SvJ * C57BL/6)

cardiovascular system phenotype

homeostasis/metabolism phenotype

integument phenotype

mortality/aging

muscle phenotype

renal/urinary system phenotype

respiratory system phenotype

References

Additional - Gpr4tm1Witt related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Gpr4^tm1Witt

Allele Symbol: Gpr4^tm1Witt

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

Additional - Gpr4^tm1Witt related