Mice that are homozygous for the Smn targeted mutant lacZ reporter allele and homozygous for the two transgenic alleles exhibit symptoms and neuropathology similar to patients afflicted with proximal spinal muscular atrophy (SMA). Triple homozygous mice on the FVB/N genetic background are noticeably smaller than normal littermates at birth and show progressive muscle weakness.
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Arthur H.M. Burghes, The Ohio State University
Genetic Background | Generation |
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N6+F41
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Reporter, Null/Knockout) | Smn1 | survival motor neuron 1 |
Allele Type |
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Transgenic (Hypomorph, Inserted expressed sequence, Humanized sequence) |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
Starting at:
$270.00 Domestic price for female 4-week |
540.00 Domestic price for breeder pair |
This triple mutant mouse harbors two transgenic alleles and a single targeted mutant. The Tg(SMN2*delta7)4299Ahmb allele consists of a SMA cDNA lacking exon 7 whereas the Tg(SMN2)89Ahmb allele consists of the entire human SMN2 gene. Mice that are homozygous for the targeted mutant Smn allele and homozygous for the two transgenic alleles exhibit symptoms and neuropathology similar to patients afflicted with proximal spinal muscular atrophy (SMA). At birth, triple mutants are noticeably smaller than normal littermates. By day 5, signs of muscle weakness are apparent and become progressively more pronounced over the following week as the mice display an abnormal gait, shakiness in the hind limbs and a tendency to fall over. In 2006, mean survival was originally reported to be ~13 days. Cohorts tested at The Jackson Laboratory in 2013 show death by ~15-22 days (mean survival of 17.7 days).
Immunocytochemical analysis indicates that dystrophin expression is normal, however fibers isolated from the gastrocnemius muscle of a 14 day old triple mutant clearly show evidence of atrophy.
Importation of this model was supported by the Spinal Muscular Atrophy Foundation. Creation and development was supported by the National Institutes of Health, the Deutsche Forschungsgemeinschaft to M.S., Families of SMA, the Preston fund, the Madison fund, the Mathew fund and the Muscular Dystrophy Association of America.
The targeted mutant allele was created in the laboratory of Dr. Michael Sendtner at the University of Wurzburg, Germany. Exon 2 of the endogenous mouse Smn gene was disrupted by employing a targeting vector encoding a neomycin cassette and a lacZ gene fused to the first 40 nucleotides of the disrupted exon to permit expression of the lacZ gene in tissues where Smn is normally expressed. The construct was electroporated into 129P2/OlaHsd-derived E14Tg2a-IV embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and chimeric animals obtained. Chimeric animals were crossed to C57BL/6 for an unspecified number of generations.
The transgenic alleles were created in the laboratory of Dr. Arthur Burghes at Ohio State University. A 35.5 kb BamHI genomic fragment encoding the human SMN2 promoter and gene (derived from genomic clone PAC215P15) was injected into fertilized FVB/N mouse oocytes and founder animal 89 was obtained. Similarly, a human SMN2 cDNA (SMNdelta7) lacking exon 7 under the control of the human SMN2 promoter was microinjected into fertilized FVB/N oocytes and founder animal 4299 was obtained. Founder animal 89 was mated to mice heterozygous for the targeted mutation of the endogenous mouse Smn gene. These double mutants were in turn mated with mice bearing the SMNdelta7 transgenic allele. The triple mutant was then backcrossed to FVB/N for at least 6 generations.
Expressed Gene | lacZ, beta-galactosidase, E. coli |
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Site of Expression | The expression of the lacZ gene in tissues where Smn is normally expressed was noted. |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Site of Expression | Grm7Tg(SMN2)89Ahmb |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Site of Expression | Tg(SMN2*delta7)4299Ahmb |
Allele Name | targeted mutation 1, Michael Sendtner |
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Allele Type | Targeted (Reporter, Null/Knockout) |
Allele Synonym(s) | SMN- |
Gene Symbol and Name | Smn1, survival motor neuron 1 |
Gene Synonym(s) | |
Expressed Gene | lacZ, beta-galactosidase, E. coli |
Site of Expression | The expression of the lacZ gene in tissues where Smn is normally expressed was noted. |
Strain of Origin | 129P2/OlaHsd |
Chromosome | 13 |
Molecular Note | A lacZ-neo cassette was inserted into exon 2 by homologous recombination resulting in an in-frame fusion of lacZ to exon 2. Homozygous mutant embryos were identified up to 80 hours post coitum. The expression of the lacZ gene in tissues where Smn is normally expressed was noted. |
Mutations Made By | Michael Sendtner |
Allele Name | transgene insertion 89, Arthur H M Burghes |
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Allele Type | Transgenic (Hypomorph, Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | SMN2; Tg(SMN2)89Ahmb |
Gene Symbol and Name | Grm7, glutamate receptor, metabotropic 7 |
Gene Synonym(s) | |
Promoter | SMN2, survival of motor neuron 2, centromeric, human |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Site of Expression | Grm7Tg(SMN2)89Ahmb |
Strain of Origin | FVB/N |
Chromosome | 6 |
Molecular Note | A 35.5 kb genomic fragment containing the human survival motor neuron 2 (SMN2) gene and promoter was used for the transgene. The transgene is ubiquitously expressed in all tissues examined by Northern blot analysis. Line 89 carries 1 copy of the transgene integrated into intron 4 of the gene. RT-PCR confirmed reduced expression of the gene the transgene is integrated into. |
Mutations Made By | Arthur Burghes, The Ohio State University |
Allele Name | transgene insertion 4299, Arthur H M Burghes |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | SMNdelta7; Tg(SMN1*delta7)4299Ahmb |
Gene Symbol and Name | Tg(SMN2*delta7)4299Ahmb, transgene insertion 4299, Arthur H M Burghes |
Gene Synonym(s) | |
Promoter | SMN2, survival of motor neuron 2, centromeric, human |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Site of Expression | Tg(SMN2*delta7)4299Ahmb |
Strain of Origin | FVB/N |
Chromosome | UN |
Molecular Note | The transgene contains a human SMN2 promoter and a human SMN2 cDNA (SMNdelta7) that lacks exon 7. There are 14 copies of this allele integrated into the genome. |
Mutations Made By | Arthur Burghes, The Ohio State University |
The Tg(SMN2)89 transgene insertion into the glutamate receptor metabotropic 7 locus (Grm7Tg(SMN2)89Ahmb) on chromosome 6, the Smn1 null targeted mutation (Smn1tm1Msd) on chromosome 13 and the randomly inserted Tg(SMN2*delta7)4299Ahmb transgene are not linked and will segregate independently.
Breeding pairs offered by The Jackson Laboratory Repository are homozygous for both transgenes (Δ7SMN+/+;SMN2+/+) and either heterozygous for the null allele (Smn+/-) or wildtype at the Smn1 locus (Smn+/+). These breeding pairs are phenotypically normal and do not exhibit symptoms of neuropathology.
Offspring resulting from the mating of breeder pairs can possess the following genotypes:
1. Homozygous for both transgenes and heterozygous for the null allele (Δ7SMN+/+;SMN2+/+;Smn+/- - 50%)
2. Homozygous for both transgenes and wildtype at the Smn1 locus (Δ7SMN+/+;SMN2+/+;Smn+/+ - 50%)
Mice that are homozygous for the Smn1 null allele, Tg(SMN2)89 and Tg(SMN2*delta7)4299Ahmb will display the SMA-like phenotype. Mice heterozygous for the Smn1 null allele and homozygous for Tg(SMN2)89 and Tg(SMN2*delta7)4299Ahmb will not display the SMA-like phenotype - but can be mated with each other to generate additional affected mice. Mice wildtype at the Smn1 locus and homozygous for Tg(SMN2)89 and Tg(SMN2*delta7)4299Ahmb will also not exhibit an SMA-like phenotype - but can be employed as control mice depending on the nature of the experiment.
When using the FVB.SMNΔ7;SMN2;Smn- , Moderate Type II SMA , Delta 7 mouse incipient congenic mouse strain in a publication, please cite the originating article(s) and include JAX stock #005025 in your Materials and Methods section.
Service/Product | Description | Price |
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Homozygous for Tg(SMN2*delta7)4299Ahmb, Homozygous for Tg(SMN2)89Ahmb, Heterozygous for Smn1<tm1Msd> |
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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.
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