Overview

Retinal arterial development in VEGF¹⁸⁸ mice is impaired. Homozygotes exhibit reduced fertility, smaller litter sizes and some prenatal lethality. This mutant mouse strain may be useful in studies of retinal angiogenesis.

Donating Investigator

Patricia D'Amore, Schepens Eye Research Institute

Genetic overview

Genetic Background	Generation

Vegfa^tm4Pec

Allele Type	Gene Symbol	Gene Name
Targeted	Vegfa	vascular endothelial growth factor A

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Research Applications

Developmental Biology Research
Reproductive Biology Research
Sensorineural Research

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Details

Detailed Description

Heterozygote: Heterozygote phenotype is similar to the wild-type phenotype.

Homozygote: Mice homozygous for the targeted mutation are viable, but exhibit reduced fertility, smaller litter sizes and some prenatal lethality. Surviving homozygotes gain less weight than wild-type controls. Retinal arterial development in VEGF¹⁸⁸ mice is impaired. By post natal day 5 (P5), only half the normal number of large vessels (mostly venules) are present in the vascular bed of the retina. By P9, arterioles are observed to be smaller in size and only 50% have developed and grown out over 17% of the retina. In controls, 88% of the retinal radius is covered by P9. Venous and capillary development appears normal.
VEGF¹⁸⁸ mice express a VEGF protein with all eight exons that avidly binds to the cell surface and extracellular matrix. This mutant mouse strain may be useful in studies of retinal angiogenesis.

Development

A targeting vector was designed to insert a loxP-flanked neomycin cassette into the 3' UTR of a cDNA containing fused exons 4 through 8. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1 derived R1 embryonic stem (ES) cells. Transient Cre expression in targeted cells excised the neo cassette. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were bred to C57BL/6 and then maintained by sibling mating. The VEGF¹⁸⁸ isoform contains all 8 exons. Upon arrival, mice were bred to C57BL/6J for at least 1 generation to establish the colony.

Selected References

Stalmans I; Ng YS; Rohan R; Fruttiger M; Bouche A; Yuce A; Fujisawa H; Hermans B; Shani M; Jansen S; Hicklin D; Anderson DJ; Gardiner T; Hammes HP; Moons L; Dewerchin M; Collen D; Carmeliet P; D'Amore PA. 2002. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109(3):327-36PubMed: 11827992 MGI: J:75507

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Genetics

Vegfa^tm4Pec

Allele Symbol: Vegfa^tm4Pec

Allele Name	targeted mutation 4, Peter Carmeliet
Allele Type	Targeted
Allele Synonym(s)	VEGF¹⁸⁸
Gene Symbol and Name	Vegfa, vascular endothelial growth factor A
Gene Synonym(s)
Promoter	Vegfa, vascular endothelial growth factor A, mouse, laboratory
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	17
Molecular Note	Genomic sequence containing exons 4 through 8 was replaced with corresponding cDNA. The resultant allele lacks splice sites and thereby produces a single isoform with high receptor binding properties. The exclusive presence of this isoform was verified by quatitative RT-PCR.
Mutations Made By	Dr. Peter Carmeliet, University of Leuven

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

DiGeorge syndrome

Research Areas By Phenotype

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

Developmental Biology Research
- Internal/Organ Defects
  - vasculature
Reproductive Biology Research
- Fertility Defects
Sensorineural Research
- Eye Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Vegfa^tm4Pec/Vegfa^tm4Pec
involves: 129S1/Sv * 129X1/SvJ

cardiovascular system phenotype

persistent truncus arteriosis

abnormal blood vessel morphology
- about 50% of neonates exhibit severe DiGeorge syndome-like vessel malformations
- vascular defects are so severe in 19% of embryos that they cause circulatory collapse by E13.5

double aortic arch
- malformations of the 4th arch artery include a double aortic arch

interrupted aortic arch
- malformations of the 4th arch artery include type-B left 4th aortic arch interruption

abnormal fourth pharyngeal arch artery morphology
- variable defects
- malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta

abnormal retinal vasculature morphology
- capillary pruning is decreased, resulting in a more dense capillary bed and a slight increase in the number of periendothelial cells per retinal cell
- at P9, only half the normal number of arterioles develop, they are smaller in size, and grow out over only 17% of the retina

abnormal pharyngeal arch artery morphology
- E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
- while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist
- in E9.5 embryos, the arch arteries appear as primitive capillary networks, often with an irregular small lumen and signs of regression (19%)

abnormal sixth pharyngeal arch artery morphology
- variable defects

abnormal vascular regression
- exhibit signs of regression in vessels of the pharyngeal arch that should normally persist

persistent right dorsal aorta
- about 10% of embryos exhibit a dominant right dorsal aorta

retroesophageal right subclavian artery
- malformations of the 4th arch artery include retroesophageal right subclavian artery

abnormal arteriole morphology
- arterioles, but not venules, in the retina are smaller and extend over only 18% of the vascular bed (compared to 90% in controls)

abnormal third pharyngeal arch artery morphology
- variable defects

pulmonary trunk hypoplasia
- hypoplasia of the pulmonary trunk

right aortic arch
- malformations of the 4th arch artery include a right-sided aortic arch

ventricular septal defect
- ventricular septal defect

cellular phenotype

abnormal vascular regression
- exhibit signs of regression in vessels of the pharyngeal arch that should normally persist

craniofacial phenotype

pharyngeal arch hypoplasia
- the first three pharyngeal arches are hypoplastic in 19% of E9.5 embryos

abnormal pharyngeal arch artery morphology
- E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
- in E9.5 embryos, the arch arteries appear as primitive capillary networks, often with an irregular small lumen and signs of regression (19%)
- while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist

abnormal sixth pharyngeal arch artery morphology
- variable defects

abnormal fourth pharyngeal arch artery morphology
- variable defects
- malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta

abnormal third pharyngeal arch artery morphology
- variable defects

embryo phenotype

abnormal pharyngeal arch artery morphology
- while the 3rd, 4th and 6th pharyngeal arch arteries are present by E10-10.5, subsequent malformations include hypoplasia, an irregular lumen size, and signs of regression in vessels that should normally persist
- E14.5 embryos and neonates have remodeling defects of the 4th, 6th and, less frequently, 3rd pharyngeal arch arteries
- in E9.5 embryos, the arch arteries appear as primitive capillary networks, often with an irregular small lumen and signs of regression (19%)

abnormal third pharyngeal arch artery morphology
- variable defects

abnormal fourth pharyngeal arch artery morphology
- malformations of the 4th arch artery include a persistence of the carotid duct segment between the left carotid and subclavian artery and a descending aorta
- variable defects

pharyngeal arch hypoplasia
- the first three pharyngeal arches are hypoplastic in 19% of E9.5 embryos

abnormal sixth pharyngeal arch artery morphology
- variable defects

growth/size/body region phenotype

decreased body weight
- surviving mice gain less weight at 7 weeks of age

mammalian phenotype

respiratory system phenotype
- Normal - neonates display normal pulmonary development

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance
- about half die between E9.5 and E13.5 and the rest survive for prolonged periods after birth

reproductive system phenotype

decreased litter size

reduced fertility
- fewer number of litters during 4 months

vision/eye phenotype

abnormal retinal vasculature morphology
- capillary pruning is decreased, resulting in a more dense capillary bed and a slight increase in the number of periendothelial cells per retinal cell
- at P9, only half the normal number of arterioles develop, they are smaller in size, and grow out over only 17% of the retina

References

Stalmans I; Ng YS; Rohan R; Fruttiger M; Bouche A; Yuce A; Fujisawa H; Hermans B; Shani M; Jansen S; Hicklin D; Anderson DJ; Gardiner T; Hammes HP; Moons L; Dewerchin M; Collen D; Carmeliet P; D'Amore PA. 2002. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109(3):327-36PubMed: 11827992 MGI: J:75507

Additional - Vegfa^tm4Pec related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Vegfa
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as heterozygotes or homozygotes, however, homozygotes occur at a lower than Mendelian ratio (12%) than expected.
- Additional Breeding and Husbandry Support
Citation
When using the B6;129-Vegfa^tm4Pec/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34406 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

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

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Selected References

Vegfatm4Pec

Allele Symbol: Vegfatm4Pec

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Vegfatm4Pec/Vegfatm4Pecinvolves: 129S1/Sv * 129X1/SvJ

cardiovascular system phenotype

cellular phenotype

craniofacial phenotype

embryo phenotype

growth/size/body region phenotype

mammalian phenotype

mortality/aging

reproductive system phenotype

vision/eye phenotype

References

Additional - Vegfatm4Pec related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Vegfa^tm4Pec

Allele Symbol: Vegfa^tm4Pec

Genotype: Vegfa^tm4Pec/Vegfa^tm4Pec
involves: 129S1/Sv * 129X1/SvJ

Additional - Vegfa^tm4Pec related