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Read More +Genetic Background | Generation |
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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 | Gene Symbol | Gene Name |
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Targeted (Inserted expressed sequence, Humanized sequence) | Smn1 | survival motor neuron 1 |
The Jackson Laboratory will not distribute triple mutant mice. Instead, we will distribute the individual lines; that is, females homozygous for the Tg(SMN2)89 transgene and heterozygous for Smn1tm1Msd (see Stock No. 007949) and males heterozygous for Smn1tm5(Smn1/SMN2)Mrph (see Stock No. 008604).
Stock No. 014561 breeding pairs allow a researcher to generate FVB.SMN2;Smn1-/C mice; the FVB/NJ-congenic Burgheron SMA model strain with one copy of the Tg(SMN2)89 transgene and are compound heterozygous at the Smn1 locus for the Smn1 null allele and Smn1 allele C (Smn1-/C).
Compound heterozygous (Smn1-/C) animals harbor the Smn1 null targeted mutation (Smn1tm1Msd; also called Smn1-) on one homologous chromosome, and the Smn1 allele C (Smn1tm5(Smn1/SMN2)Mrph; also called Smn1C) on the other homologous chromosome. Smn1-/C mice have an intermediate level of SMN expression that falls between that of Smn1-/- and Smn1C/C.
The phenotype of FVB.SMN2;Smn1-/C mice is the intermediate type II/III Spinal Muscular Atrophy. Mean survival is ~98.5 days for females and ~102 days for males. Tail necrosis leads to tail loss by ~45 days of age. Other characteristic SMA phenotypes in the Burgheron model include cardiomyopathy, reduced numbers of functional motor units, and delayed neuromuscular junction maturation.
The phenotype of the parental mouse lines used to generate FVB.SMN2;Smn1-/C mice (Stock No. 014561) are each briefly described below.
FVB/N-congenic mice homozygous for the Tg(SMN2)89 transgene (SMN2+/+), and homozygous for the Smn1tm1Msd mutation (Smn-/-) are a severe Type I SMA mouse model (Stock Nos. 005024 and 007949). FVB.SMN2+/+;Smn-/- mice exhibit perinatal and complete embryonic lethality that worsens with increased backcross generations onto FVB/NJ. Also note, Stock No. 005024 does not survive as hemizygous for the Tg(SMN2)89 transgene and homozygous for the Smn1 null allele.
The Smn1C hybrid allele contains two tandem Smn1/SMN2 genes. Homozygous FVB/N-congenic Smn1C/C mice (Stock No. 008604) exhibit a mild SMA phenotype due to the preferential splicing of the Δ7-SMN gene product over the full-length SMN product.
FVB.SMN2;Smn1-/C mice harbor the Tg(SMN2)89 transgene and are compound heterozygous for the the Smn1 null allele and Smn allele C. The Jackson Laboratory will not distribute animals with this genotype. Instead, we will distribute as the following breeding pair: females homozygous for the Tg(SMN2)89 transgene (SMN2+/+) and heterozygous for the Smn1tm1Msd null allele (Smn+/-) and males heterozygous for the Smn1tm5(Smn1/SMN2)Mrph allele (Smn1C/+). Each component is described below.
The creation of the Tg(SMN2)89 transgene (SMN2) and Smn1 null targeted mutation (Smn1tm1Msd; also called Smn1-) are described for the severe type I SMA mouse model on an FVB/NJ fully congenic background; Stock No. 007949. Note the Tg(SMN2)89 transgene insertion site in on chromosome 6. Stock No. 007949 is bred to and maintained upon an FVB/NJ-congenic background.
The creation of the Smn1 allele C (Smn1tm5(Smn1/SMN2)Mrph; also called Smn1C) is described as Stock No. 008604. Briefly, the Smn1C contains two tandem Smn1/SMN2 genes. Stock No. 008064 is maintained upon an FVB/NJ-congenic background.
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 |
Expressed Gene | Smn1, survival motor neuron 1, mouse, laboratory |
Site of Expression | Smn1 is normally expressed in motor neurons, particularly in the spinal chord. |
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 | targeted mutation 5, Andrew Murphy |
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Allele Type | Targeted (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | Smn allele C |
Gene Symbol and Name | Smn1, survival motor neuron 1 |
Gene Synonym(s) | |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Expressed Gene | Smn1, survival motor neuron 1, mouse, laboratory |
Site of Expression | Smn1 is normally expressed in motor neurons, particularly in the spinal chord. |
Strain of Origin | (129S6/SvEvTac x C57BL/6NTac)F1 |
Chromosome | 13 |
Molecular Note | The allele encodes two coding sequences: the first is a hybrid gene in which a 2.2 kb segment of mouse genome containing exons 7 and 8 of the mouse Smn1 gene was replaced with a 1.3 kb fragment of human genomic DNA containing exons 7 and 8 of the human SMN2 gene and the second is a full 42 kb copy of the human SMN2 gene. A selection cassette located downstream from the human SMN2 polyadenylation signal was removed by FLPe expression in ES cells leaving a FRT site at the downstream junction between human and mouse DNA. Because exon 7 is derived from human SMN2, it is skipped in approximately 90% of the processed mRNA derived from both genes. 2 independent clones for this allele were generated and clone A2 was used to generated mice. |
Mutations Made By | Andrew Murphy, Regeneron Pharmaceuticals, Inc. |
The Tg(SMN2)89 transgene on chromosome 6 and the Smn1 targeted mutations on chromosome 13 are not linked and will segregate independently.
FVB.SMN2;Smn1-/C mice harbor the Tg(SMN2)89 transgene and are compound heterozygous for the the Smn1 null allele and Smn allele C. The Jackson Laboratory will not distribute animals with this genotype. Instead, breeding pairs offered by The Jackson Laboratory Repository are females homozygous for the Tg(SMN2)89 transgene (SMN2+/+) and heterozygous for the Smn1tm1Msd null allele (Smn+/-) and males heterozygous for the Smn1tm5(Smn1/SMN2)Mrph allele (Smn1C/+).
These breeding pairs are phenotypically normal and do not exhibit symptoms of neuropathology.
Offspring resulting from the mating of these breeder pairs can possess the following genotypes:
1. SMN2;Smn1-/C: Hemizygous for the transgene and compound heterozygous at the Smn1 locus for the Smn1 null allele and Smn1 allele C (25%)
2. SMN2;Smn1+/-: Hemizygous for the transgene and heterozygous for the Smn1 null allele (25%)
3. SMN2;Smn1C/+: Hemizygous for the transgene and heterozygous for the Smn1 allele C (25%)
4. SMN2;Smn1+/+: Hemizygous for the transgene and wildtype for both Smn1 targeted mutations (25%)
Mice that are hemizygous for the transgene and compound heterozygous will display the SMA-like phenotype.
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