STOCK Fxn^tm1Mkn Tg(FXN)Y47Pook/J

Stock number: 024097
Product name: Y47R
Strain synonyms: YG47R
Research areas: Neurobiology Research

Description

This human FXN YAC transgenic mouse model carries the mouse frataxin knockout allele (Fxn^-) and a single copy integration of the Y47 human FXN YAC transgene (encoding human frataxin with normal-sized (GAA)₉ repeats). Mice homozygous for the knockout and hemizygous for the Y47 transgene, called Y47R mice, are rescued from the embryonic lethality of frataxin-deficiency. Y47R is a control strain to be used with human FXN YAC transgenic models with expanded GAA repeats that lead to Friedreich's Ataxia pathology (such as (YG22R, YG8R and YG8sR).

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Detailed description

This human FXN YAC transgenic mouse model carries the mouse frataxin knockout allele (Fxn^-) and a single copy integration of the Y47 human FXN YAC transgene (encoding human frataxin with normal-sized (GAA)₉ repeats). The donating investigator reports that agarose gel analysis shows the (GAA)₉ repeat sequence to be stable through several generations of breeding. Mice homozygous for the knockout and hemizygous for the Y47 transgene (called Y47R mice) are rescued from the embryonic lethality of frataxin-deficiency. Y47R mice and are viable and fertile with normal lifespan and no Friedreich's Ataxia (FRDA)-like pathology. Y47R is a control strain to be used with human FXN YAC transgenic models with expanded GAA repeats that lead to FRDA pathology, such as (YG22R, YG8R and YG8sR. Of note, Y47R mice have a progressive gain in weight compared to C57BL6/J mice (which may affect rotarod performance from 9-12 months of age).

Development

This human FXN YAC transgenic mouse model carries the mouse frataxin knockout allele (Fxn^+/-) and the Y47 human FXN YAC transgene. When homozygous for the knockout and hemizygous for the transgene, these mice are called Y47R. Specific details below.

The frataxin knockout allele (Fxn^tm1Mkn) was designed by Drs. Michel Koenig and Helene Puccio to disrupt exon 4 and flanking sequences of the frataxin locus on chromosome 19 with a loxP-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, and then backcrossed to wildtype C57BL/6J mice. Heterozygous mice (Fxn^+/-) were used as described below. C57BL/6J-congenic frataxin knockout mice are described and available from The Jackson Laboratory as Stock No. 016842.

The Y47 human FXN YAC transgene was created by Dr. Mark A. Pook by first obtaining the 370 kbp YAC (Y37FA12) that includes the entire human FXN gene with nine GAA repeats [(GAA)₉] at the mutation locus within intron 1 of FXN. The GAA repeat expansion was not further modified, and the YAC transgene was injected into the pronuclei of (C57BL/6 x CBA)F1 fertilized oocytes. Founder animals were bred to wildtype C57BL/6J mice. Founder line Y47 was established and backcrossed to wildtype C57BL/6J mice. Y47 mice have a single copy integration of the transgene. Dr. Pook bred Y47 and Fxn^+/- mice together to generate the Y47R human FXN YAC transgenic mouse model. In 2014, Dr. Pook sent Y47R animals on a "mixed-but-predominantly C57BL/6J" genetic background to The Jackson Laboratory as Stock No. 024097. Upon arrival, sperm was cryopreserved. To establish our living colony, an aliquot of the frozen sperm was used to fertilize oocytes from Fxn^+/- females (Stock No. 016842).

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.

Allele

Symbol: Tg(FXN)Y47Pook
Name: transgene insertion Y47, Mark A Pook
MGI accession ID: MGI:5585461
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(FXN)Y47Pook
Marker name: transgene insertion Y47, Mark A Pook
Chromosome: UN
Strain of origin: (C57BL/6 x CBA)F1
Expressed genes: FXN,frataxin,human
Site of expression: The Y47 human FXN YAC transgene contains the entire human FXN gene with nine GAA repeats [(GAA)₉] at the mutation locus within intron 1 of FXN.
Molecular note: The transgene construct consists of a 370 kbp YAC (Y37FA12) that includes the entire human FXN gene with nine GAA repeats [(GAA)>9<] at the mutation locus within intron 1 of FXN. The GAA repeat expansion was not further modified. Founder line Y47 was established and contains a single copy integration of the transgene.