B6.129(Cg)-Fxn^tm1Mkn/J

Stock number: 016842
Research areas: Developmental Biology Research, Neurobiology Research

Description

These Frda^del4 Fxn knockout mice exhibit an embryonic lethal phenotype and are useful in studies of in studies of Friedreich's ataxia.

 

Detailed description

Frataxin mitochondrial protein, which is encoded by the Fxn gene, regulates mitochondrial iron transport and respiration. Expansion of the intronic GAA nucleotide repeat causes Friedreich's ataxia. These Frda^del4 mice carry a knock out mutation for the Fxn gene in which exon 4 has been replaced by a floxed PGK-NEO cassette. Mice that are heterozygous for the targeted mutation are viable and fertile. No gene product (protein) is detected by Western blot analysis of rescued double mutant mice that are homozygous for this null allele and are carrying the Tg(FXN)Y47Pook transgene (see Stock#024097). Homozygous null mice have an early post-implantation lethal phenotype, and are resorbed by E9.5. By E7, homozygous embryos and extra-embryonic tissues are smaller in size than wildtype controls. At E6.75 and E7.5, homozygous embryos exhibit pycnotic nuclei and condensed chromatin; extra-embryonic regions exhibit clusters of apoptotic TUNEL-positive cells. Necrotic cells are also observed.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Importation of this model was supported by the Friedreich's Ataxia Research Alliance (FARA).

Development

Drs. Michel Koenig and Helene Puccio generated the Fxn targeted mutation allele by disrupting exon 4 and flanking sequences with a loxP site flanked PGK-neo cassette. The construct was electroporated into 129/Sv derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice. The mice were crossed to a transgenic line on the C57BL/6 background, and the double mutant mice were backcrossed to C57BL/6J using a speed congenic protocol. The mice were then bred to remove the transgene.

Allele

Symbol: Fxn^tm1Mkn
Name: targeted mutation 1, Michel Koenig
MGI accession ID: MGI:2177162
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Fxn
Marker name: frataxin
Chromosome: 19
Strain of origin: 129/Sv
Expressed genes: Fxn,frataxin,mouse, laboratory
Molecular note: A loxP-flanked PGK-neomycin resistance cassette replaced a genomic DNA fragment containing exon 4, which is highly conserved and often mutated in humans. An additional line was also produced in which the loxP flanked neomycin cassette was removed by Cre mediated recombination, but no distinction was made between these alleles in the original reference. From J:90098: The presence of a human FRDA transgene in hemizygous form in a Frda^tm1Mkn homozygous null background rescues the embryonic lethal phenotype and complements for the loss of endogenous mouse frataxin.