B6;129S2-Trp53^tm1Tyj Nf1^tm1Tyj/J

Stock number: 008191
Research areas: Apoptosis Research, Cancer Research, Developmental Biology Research, Immunology, Inflammation and Autoimmunity Research, Mouse/Human Gene Homologs, Research Tools

Description

These mice carry Trp53 and Nf1 targeted mutations on the same homolog of chromosome 11 (in cis). These mutations are approximately 10 Mbp apart and may segregate independently of one another. Double heterozygotes survive an average of five months and exhibit a significant increase in the percentage of soft tissue sarcomas. About 30% of tumors from the Nf1/Trp53 cis animals stain positively for S100 (consistent with glial cell origin) and exhibit classic histological features of malignant peripheral nerve sheath tumors (MPNSTs). This strain may be useful in studies of astrocytomas/glioblastomas and tumor suppressor genes.

Detailed description

These mice carry Trp53 and Nf1 targeted mutations (in cis) on chromosome 11. These mutations are approximately 10 Mbp apart and may segregate independently of one another. Double homozygotes are embryonic lethal. Double heterozygotes survive an average of five months and exhibit a significant increase in the percentage of soft tissue sarcomas compared with mice of other genotypes (Nf1 +/-, 5%; p53, 57%; Nf1/Trp53 trans, 36%; Nf1/Trp53 cis, 81%). Furthermore, although Nf1/Trp53 trans mice exclusively develop osteo-, fibro-, rhabdomyo-, and hemangiosarcomas, about 30% of tumors from the Nf1/Trp53 cis animals stain positively for S100 (consistent with glial cell origin) and exhibit classic histological features of malignant peripheral nerve sheath tumors (MPNSTs). This strain may be useful in studies of astrocytomas/glioblastomas and tumor suppressor genes.

Development

These mice carry two independently-created targeted mutations, Trp53^tm1Tjy and Nf1^tm1Tyj, that are approximately 10 Mbp apart on the same homolog of chromosome 11 (in cis). To create the Trp53 mutation, a targeting vector was designed to replace approximately 40% of the coding sequences (involving exons 2-6) with a neomycin resistance cassette. To create the Nf1 mutation, a targeting vector was designed to insert a neomycin resistance cassette and delete the first 42 codons of exon 31, the exon 31 splice acceptor site, and approximately 2 kb of intron 30. Each of the targeting vectors was independently electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Independent strains carrying germline mutations in Trp53 and Nf1 were generated on a mixed 129S2/SvPas and C57BL/6 genetic background, and then then intercrossed. Mice that underwent meiotic recombination events placing both mutations on the same homolog of chromosome 11 (in cis) were selected. This double mutant strain was maintained on a mixed 129S2/SvPas and C57BL/6 genetic background by the donating laboratory prior to sending to The Jackson Laboratory Repository. Upon arrival, males that were heterozygous for both mutations were identified and used to cryopreserve sperm.

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 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: 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.