B6;129-Trp53^tm1Tyj Nf1^tm1Tyj Suz12^{Gt(Betageo)1Khe}/KcichJ

Stock number: 027678
Product name: Nf1/p53/Suz12
Research areas: Apoptosis Research, Cancer Research, Immunology, Inflammation and Autoimmunity Research, Mouse/Human Gene Homologs, Research Tools

Description

These NPS+/- mice carry Trp53, Nf1, and Suz12 mutations on chromosome 11 (in cis) and develop high-grade gliomas and malignant peripheral nerve sheath tumors by approximately 3.5 months. They are suitable for use in applications related to the study of neurofibromatosis type 1 and tumor suppressor genes.

Detailed description

These NPS+/- mice carry Trp53, Nf1, and Suz12 mutations on chromosome 11 (in cis), which is similar to conditions found in some human neurofibromatosis type 1 patients. Triple homozygotes are embryonic lethal. By 3 months of age, more than half (54%) of mice heterozygous for all 3 alleles, in cis, develop high-grade gliomas. Triple heterozygotes develop malignant peripheral nerve sheath tumors by 3.5 months of age, develop histiocytic sarcoma, lymphoma, and angiosarcoma, and have a shortened lifespan (approximately 5 months).

Development

This triple mutant line was generated by intercrossing the single mutant lines to obtain triple heterozygotes with all 3 alleles in cis on chromosome 11. Mice that underwent meiotic recombination events placing all 3 mutations on the same homolog of chromosome 11 (in cis) were selected.

For the Trp53^tm1Tyj allele: a targeting vector was designed to replace approximately 40% of the coding sequences (involving exons 2-6) with a neomycin resistance cassette. The construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice. It is not known if the mice were backcrossed to C57BL/6 mice. The Donating Investigator obtained the mice from The Jackson Laboratory.

For the Nf1^tm1Tyj allele: a targeting vector was use to replace the first 42 codons of exon 31, the exon 31 splice acceptor site, and approximately 2 kb of intron 30 with a neomycin resistance cassette (oriented in an opposite transcriptional direction). The vector was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were tested for germline transmission. This strain was obtained by the Donating Investigator from Dr. Tyler Jacks. The mice were backcrossed to C57BL/6 background more than twelve times by the donating laboratory.

For the Suz12^{Gt(Betageo)1Khe}allele: gene trap vector containing β-GEO was inserted into intron 7, generating a truncation product of 276 N-terminal SUZ12 amino acids fused to 1323 amino acids of the β-GEO (beta-galactosidase-neomycin) protein. The vector was electroporated into unspecified 129P2/OlaHsd derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric male animals were crossed to C57BL/6 mice. It is not known if the mice were backcrossed to C57BL/6 mice. The Donating Investigator obtained the mice from Dr. Kristian Helin.

Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Trp53^tm1Tyj
Name: targeted mutation 1, Tyler Jacks
MGI accession ID: MGI:1857263
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Trp53
Marker name: transformation related protein 53
Chromosome: 11
Strain of origin: 129S2/SvPas
Site of expression: Normal Trp53 expression is widespread.
Molecular note: A neomycin resistance gene cassette replaced 40% of the coding sequences beginning with exon 2 (upstream of the translation start site) and extending into exon 6.
General note: This mutant allele was produced by a targeted neo insertion into the Trp53 locus. Homozygotes show no visible phenotype but develop tumors at 3-6 months of age. Heterozygotes develop tumors at 10 months of age. These mice model some of the features of human Li-Fraumeni syndrome (OMIM 151623), a form of familial breast cancer with mutations in TRP53 (J:16022)(J:16023) A specific human mutation found in hepatocellular carcinomas caused by hepatitis B infection or by aflatoxin exposure has been created in a mouse model, resulting in a similar gene product (J:27363).

Allele

Symbol: Suz12^{Gt(Betageo)1Khe}
Name: gene trap 1, Kristian Helin
MGI accession ID: MGI:3530650
Generation method: Gene trapped
Attributes: Reporter; Null/Knockout
Marker symbol: Suz12
Marker name: SUZ12 polycomb repressive complex 2 subunit
Chromosome: 11
Strain of origin: 129P2/OlaHsd
Expressed genes: Bgeo,fusion of beta-galactosidase and neomycin phosphotransferase genes,E. coli
Site of expression: Embryonic stem cells.
Molecular note: A gene trap vector inserted into intron 7 which created a truncation containing 276 N-terminal amino acids fused to 1323 amino acids of the Betagalactosidase-neo protein. The translated protein was functionally inactive.

Allele

Symbol: Nf1^tm1Tyj
Name: targeted mutation 1, Tyler Jacks
MGI accession ID: MGI:1857478
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Nf1
Marker name: neurofibromin 1
Chromosome: 11
Strain of origin: 129S2/SvPas
Site of expression: Nf1 is normally widely expressed.
Molecular note: A neomycin resistance cassette replaced the first 42 codons of exon 31, the exon 31 splice acceptor site, and approximately 2 kb of intron 30. This allele is a null allele; no stable full-length protein is made.