Overview

These E2f1 (E2F transcription factor 1) knockout mice exhibit late onset testicular atrophy, degenerated seminiferous tubules, abnormal submaxillary and parotid salivary glands, abnormal cells in the pancreas, late-onset weight loss and spontaneous tumors in 19% to 34% of mice. This mutant mouse strain may be useful in studies of cancer and cell cycle research.

Donating Investigator

Dr. Lili Yamasaki, Columbia University

Genetic overview

Genetic Background	Generation

E2f1^tm1Njd

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	E2f1	E2F transcription factor 1

View Genetics

Research Applications

Cancer Research
Reproductive Biology Research
Endocrine Deficiency Research

View All Research Applications

Details

Detailed Description

Homozygotes: Mice that are homozygous for the targeted mutation are viable and normal in size. Although testes appear normal at 2.5 months, by 9 months homozygous males exhibit testicular atrophy and empty, degenerated seminiferous tubules, although no decrease in Leydig cells is observed. Submaxillary and parotid salivary glands develop abnormally large and swollen cell nuclei and binucleate cells. Large nuclei and binucleate cells also are observed in the exocrine portion of the pancreas. Body weights are normal until 12 to 15 months of age when many mice develop dramatic weight loss. Spontaneous tumors develop in 19% to 34% of mice between 8 and 18 months of age suggesting a function for E2f1 in tumor suppression. Tumor types include, in order of frequency, reproductive tract sarcomas, lung tumors, lymphomas and other tumor types at lower frequencies.
This mutant mouse strain may be useful in studies of cancer and cell cycle research.

Heterozygote: Normal phenotype, although several heterozygotes develop rare reproductive tract sarcomas and lung adenocarcinomas.

Development

A targeting vector containing neomycin resistance gene in the antisense direction was used to replace a portion of exon 2 (cyclin A binding) and all of exon 3 (DNA binding). The construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to C57BL/6J and offspring were maintained by sibling mating. Upon arrival, mice were bred to C57BL/6J for at least 1 generation to establish the colony.

Control Suggestions

Approximate Controls

Wild-type from the colony
101045 B6129SF2/J

Additional Information

Considerations for Choosing Controls

Genetics

E2f1^tm1Njd

Allele Symbol: E2f1^tm1Njd

Allele Name	targeted mutation 1, Nicholas J Dyson
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	E2F-1-; E2f1-
Gene Symbol and Name	E2f1, E2F transcription factor 1
Gene Synonym(s)
Strain of Origin	129S2/SvPas
Chromosome	2
Molecular Note	All of exon 2 and part of exon 3, encoding residues critical for cyclin and DNA binding, was replaced with a neomycin cassette in antisense orientation. Immunoprecipitation and Western blot analysis demonstrated that no protein was made in fibroblasts isolated from E12.5 homozygous embryos.
Mutations Made By	Dr. Lili Yamasaki, Columbia University

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cancer Research
- Genes Regulating Growth and Proliferation
- Increased Tumor Incidence
- Tumor Suppressor Genes
Reproductive Biology Research
- Fertility Defects
  - males only
- Developmental Defects Affecting Gonads
  - males only
Endocrine Deficiency Research
- Pancreas 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: E2f1^tm1Njd/E2f1^tm1Njd
involves: 129S2/SvPas * SKH1

integument phenotype

increased sensitivity to skin irradiation
- increased sensitivity to UVB than controls at lower doses
- increased apoptotic response

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

Genotype: E2f1^tm1Njd/E2f1^tm1Njd
involves: 129S2/SvPas * C57BL/6

adipose tissue phenotype

increased adipocyte glucose uptake
- more efficient

decreased total body fat amount
- reduced total body fat mass

abnormal fat cell differentiation
- impaired adipocyte differentiation

endocrine/exocrine gland phenotype

abnormal parotid gland morphology
- abnormally large and swollen cell nuclei and many binucleate cells
- cells producing amylase are abnormal

decreased insulin secretion
- isolated islets release significantly reduced but nevertheless robust levels of insulin

abnormal submandibular gland morphology
- Normal - serous cells are normal
- fewer mucous acini compared to serous acini despite an increase in the size of individual mucous cells
- abnormalities restricted to mucous cells
- abnormally large and swollen cell nuclei and many binucleate cells

increased Leydig cell number
- interstitial cells are more numerous than normal at 2.5 months
- cell numbers remain stable or increase somewhat with age

decreased pancreas weight
- disproportionately greater reduction than body weight

decreased pancreatic islet number
- relative to body weight

abnormal salivary gland morphology
- decrease in overall size of the salivary gland complex with age
- histology deteriorates with age
- Normal - notably, mucous cells of the sublingual gland appear normal

decreased testis weight
- testis weights average 44% of controls and only 10% in most extreme instances

abnormal exocrine pancreas morphology
- decrease in size with age
- cells with enlarged or doubled nuclei
- histology deteriorates with age
- similar abnormalities to salivary glands

abnormal gland morphology

abnormal pancreas morphology

abnormal pancreatic beta cell morphology
- total beta cell area is reduced

abnormal pancreatic islet morphology
- ratio of alpha to beta cells is increased
- ratio of glucagon secreting to insulin secreting cells elevated at 16 weeks
- Normal - ratio of glucagon secreting to insulin secreting cells normal at 4 weeks of age

abnormal exorbital lacrimal gland morphology
- cells with enlarged nuclei

seminiferous tubule degeneration
- empty and degenerating tubules by 9 months becoming more obvious by 12 months

testicular atrophy
- seen between 9 and 15 months

small pancreatic islets
- reduced cross-sectional area relative to body weight

cellular phenotype

increased adipocyte glucose uptake
- more efficient

abnormal fat cell differentiation
- impaired adipocyte differentiation

growth/size/body region phenotype

decreased body weight
- body weight more or less normal up to 8.7 months
- considerable weight loss in 12-15 month old animals

homeostasis/metabolism phenotype

decreased circulating insulin level
- fasting insulin levels lower than controls

decreased circulating glucose level
- fasting glucose levels lower than in controls

impaired glucose tolerance
- reduced glucose clearance in a glucose tolerance test

abnormal circulating insulin level
- insulin levels do not increase in a glucose tolerance test

increased insulin sensitivity

decreased insulin secretion
- isolated islets release significantly reduced but nevertheless robust levels of insulin

neoplasm

increased metastatic potential
- sarcomas are very metastatic

increased lymphoma incidence
- lymphoproliferative syndrome develops in a small number of females between 8 and 15 months
- often leads to death
- involves enlarged lymph nodes, splenomegaly, glomerulonephritis, anemia (hematocrits of 8-15%)
- develop between 12.5 and 16.5 months of age

increased histiocytic sarcoma incidence

increased lung adenocarcinoma incidence

increased reproductive system tumor incidence
- endometrial stroma sarcomas
- epididymal tumors between the ducts in space normally occupied by smooth muscle or connective tissue
- about 1/3 of tumors are found in the reproductive tract

increased tumor incidence
- up to 34% of homozygotes have tumors by 15 months of age

increased lung non-small cell carcinoma incidence

reproductive system phenotype

increased Leydig cell number
- cell numbers remain stable or increase somewhat with age
- interstitial cells are more numerous than normal at 2.5 months

increased reproductive system tumor incidence
- about 1/3 of tumors are found in the reproductive tract
- endometrial stroma sarcomas
- epididymal tumors between the ducts in space normally occupied by smooth muscle or connective tissue

testicular atrophy
- seen between 9 and 15 months

seminiferous tubule degeneration
- empty and degenerating tubules by 9 months becoming more obvious by 12 months

decreased testis weight
- testis weights average 44% of controls and only 10% in most extreme instances

respiratory system phenotype

increased lung adenocarcinoma incidence

increased lung non-small cell carcinoma incidence

digestive/alimentary phenotype

abnormal exocrine pancreas morphology
- histology deteriorates with age
- decrease in size with age
- cells with enlarged or doubled nuclei
- similar abnormalities to salivary glands

abnormal submandibular gland morphology
- abnormally large and swollen cell nuclei and many binucleate cells
- Normal - serous cells are normal
- abnormalities restricted to mucous cells
- fewer mucous acini compared to serous acini despite an increase in the size of individual mucous cells

abnormal parotid gland morphology
- abnormally large and swollen cell nuclei and many binucleate cells
- cells producing amylase are abnormal

abnormal salivary gland morphology
- Normal - notably, mucous cells of the sublingual gland appear normal
- decrease in overall size of the salivary gland complex with age
- histology deteriorates with age

vision/eye phenotype

abnormal exorbital lacrimal gland morphology
- cells with enlarged nuclei

References

Additional - E2f1^tm1Njd related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:E2f1
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as heterozygotes or homozygous female x heterozygous male. Homozygous males are infertile.
- Additional Breeding and Husbandry Support
Citation
When using the B6;129S2-E2f1^tm1Njd/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #34309 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

Control Suggestions

Approximate Controls

Additional Information

E2f1tm1Njd

Allele Symbol: E2f1tm1Njd

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: E2f1tm1Njd/E2f1tm1Njdinvolves: 129S2/SvPas * SKH1

integument phenotype

Genotype: E2f1tm1Njd/E2f1tm1Njdinvolves: 129S2/SvPas * C57BL/6

adipose tissue phenotype

endocrine/exocrine gland phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

neoplasm

reproductive system phenotype

respiratory system phenotype

digestive/alimentary phenotype

vision/eye phenotype

References

Additional - E2f1tm1Njd 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

E2f1^tm1Njd

Allele Symbol: E2f1^tm1Njd

Genotype: E2f1^tm1Njd/E2f1^tm1Njd
involves: 129S2/SvPas * SKH1

Genotype: E2f1^tm1Njd/E2f1^tm1Njd
involves: 129S2/SvPas * C57BL/6

Additional - E2f1^tm1Njd related