Overview

Also Known As:Smn1^C

The Smn1^C hybrid allele contains two tandem Smn1/SMN2 genes. This mutant mouse strain may be useful in studies of Spinal Muscular Atrophy. In addition to motor deficits, SMN deficiencies in these mice may also be useful as a potential model of chronic pain.

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Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Smn1^{tm5(Smn1/SMN2)Mrph}

Allele Type	Gene Symbol	Gene Name
Targeted (Inserted expressed sequence, Humanized sequence)	Smn1	survival motor neuron 1

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The hybrid allele in this strain, Smn allele C, contains two tandem Smn1/SMN2 genes. Because exon 7 is derived from human SMN2, it is skipped in approximately 90% of the processed mRNA derived from both genes. Western blot analysis of full-length SMN in the spinal cord and liver extracts of homozygous mice (Smn1^C/C) shows reduced relative SMN total protein (mouse + human) compared with heterozygous and wildtype animals. SMN protein levels are significantly reduced in the spinal cord and liver of homozygoyes. Smn1^C/C mice exhibit a mild SMA phenotype due to the preferential splicing of the Δ7-SMN gene product over the full-length SMN product. The homozygous phenotype includes reduced body weight, peripheral necrosis (beginning with the tail and moving toward the hindlimbs and then to the pinnae of the ears), mild progressive neuromuscular junction abnormalities and electrophysiological defects, diminished open field activity, decreased bone mineral density, evidence of cardiac abnormalities and heightened nocioceptive responses. This mutant mouse strain may be useful in studies of Spinal Muscular Atrophy.

Development of this model was supported by the Spinal Muscular Atrophy Foundation.

Development

This mutant mouse carries the Smn allele C, which contains two tandem Smn1/SMN2 genes. The first is a hybrid gene in which a 2.2 kbp segment of mouse genome containing exons 7 and 8 of the mouse Smn1 gene was replaced with a 1.3 kbp fragment of human genomic DNA containing exons 7 and 8 of the human SMN2 gene. The second is a full 42 kbp 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. The (129S6/SvEvTac x C57BL/6NTac)F1 hybrid derived ES cell line F1H4 was used. The mice were crossed to C57BL/6J once, and then were backcrossed to FVB/NJ using a speed congenic protocol.

Expression Data

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.

Control Suggestions

001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Osborne M; Gomez D; Feng Z; McEwen C; Beltran J; Cirillo K; El-Khodor B; Lin MY; Li Y; Knowlton WM; McKemy DD; Bogdanik L; Butts-Dehm K; Martens K; Davis C; Doty R; Wardwell K; Ghavami A; Kobayashi D; Ko CP; Ramboz S; Lutz C. 2012. Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models. Hum Mol Genet 21(20):4431-47PubMed: 22802075 MGI: J:186987

View All References

Genetics

Smn1^{tm5(Smn1/SMN2)Mrph}

Allele Symbol: Smn1^{tm5(Smn1/SMN2)Mrph}

Allele Name	targeted mutation 5, Andrew Murphy
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.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

intermediate spinal muscular atrophy

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Neurobiology Research
- Spinal Muscular Atrophy (SMA)

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1⁺
involves: 129S6/SvEvTac * C57BL/6NTac

mammalian phenotype

no phenotypic analysis
- Normal - no phenotypic analysis available

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

behavior/neurological phenotype

decreased thermal nociceptive threshold
- 6-8 week old mutants (with no paw necrosis) exhibit an increase in sensitivity to moderately noxious heat with a significant decrease in hindpaw withdrawal latencies when placed on a 45C and 48C metal plate, however no differences in response to high noxious stimulus of 52C is seen
- 6-8 week old mutants exhibit robust sensitization in the evaporative cooling assay, responding more vigorously than controls, indicating increased sensitivity to temperature
- ous stimulus of 52C is seen

enhanced coordination
- Normal - however, forelimb grip strength is normal at 24 and 52 weeks of age
- mutants perform better than controls on the accelerated rotarod test and marginally better on the constant speed rotarod test at 1 month of age

hyperalgesia

hyperresponsive to tactile stimuli
- in plantar von Frey testing, 6-8, 20 and 24 week old mutants show significantly lower paw withdrawal force than controls, indicating hyperalgesia

cellular phenotype

epidermal necrosis
- mutants present with progressive necrosis of peripheral body parts beginning with the tail and moving toward the hindlimbs and then to the pinnae of the ears

tail necrosis
- onset of tail necrosis is seen as early as P5 and progresses to complete loss of the tail by 45 days of age
- tail necrosis at 20-40 days of age is characterized by disorganization of muscle fiber bundles along with loss of intact vasculature in the absence of an inflammatory lesion as mice age

growth/size/body region phenotype

decreased body size
- by P15 and P20, males and females, respectively, are smaller than wild-type controls

integument phenotype

decreased thermal nociceptive threshold
- 6-8 week old mutants (with no paw necrosis) exhibit an increase in sensitivity to moderately noxious heat with a significant decrease in hindpaw withdrawal latencies when placed on a 45C and 48C metal plate, however no differences in response to high noxious stimulus of 52C is seen
- 6-8 week old mutants exhibit robust sensitization in the evaporative cooling assay, responding more vigorously than controls, indicating increased sensitivity to temperature
- ous stimulus of 52C is seen

epidermal necrosis
- mutants present with progressive necrosis of peripheral body parts beginning with the tail and moving toward the hindlimbs and then to the pinnae of the ears

hyperalgesia

hyperresponsive to tactile stimuli
- in plantar von Frey testing, 6-8, 20 and 24 week old mutants show significantly lower paw withdrawal force than controls, indicating hyperalgesia

limbs/digits/tail phenotype

tail necrosis
- onset of tail necrosis is seen as early as P5 and progresses to complete loss of the tail by 45 days of age
- tail necrosis at 20-40 days of age is characterized by disorganization of muscle fiber bundles along with loss of intact vasculature in the absence of an inflammatory lesion as mice age

muscle phenotype

decreased skeletal muscle fiber size

nervous system phenotype

abnormal endplate potential
- at P350, 15% of junctions in splenius muscles are silent in the functional junctions that remain
- at P90, about 8% of junctions in splenius muscle are silent, where MEPPs could be recorded, but nerve stimulation did not elicit endplate potentials (EPPs)

abnormal miniature endplate potential
- at P90 and P350, muscle exhibits a slight increase in the spontaneous miniature endplate potential (MEPP) amplitude
- Normal - however, no difference from controls is seen in the MEPP frequency or the evoked endplate potential (EPP) amplitudes
- upon nerve stimulation, the quantal content is decreased by 13-14% in both mutants at P90 and P350

abnormal neuromuscular synapse morphology
- at P90, about 10% of neuromuscular junctions (NMJs) in splenius, longissimus, and semispinalis muscles show abnormal morphology, with fragmented acetylcholine receptor clusters, abnormal thin nerve terminals, some junctions innervated by multiple nerve terminals, and nerve terminal sprouting, indicating that synaptic maintenance is mildly disrupted
- Normal - however, at P8 and P14, all NJMs are innervated and no nerve sprouting is seen, indicating that synapse formation at the NJM is not affected in mutants
- rminals, and nerve terminal sprouting, indicating that synaptic maintenance is mildly disrupted

abnormal synaptic transmission
- Normal - however, mutants exhibit normal number of motor axons in the lumbar 3 and lumbar 4 ventral roots at P350 and no significant loss of VGLUT1-positive synapses in L1-2 motoneurons
- reduction in synaptic transmission efficacy in muscle

cardiovascular system phenotype

abnormal blood vessel morphology
- lateral vasculature of the tail is primarily affected, with a loss of integrity in the vessel wall (most evident in the inner tunica intima of the small lateral vasculature) whereas the ventral artery remains intact until the very last stages of necrosis
- thermal imaging indicates that vascular destruction in the tail occurs before overt exterior necrosis

decreased heart rate
- 9 month old mutants exhibit lower average heart rate than controls
- Normal - however, mutants do not exhibit a longer PR or QRS interval, indicating that mutants do not exhibit bradyarrhythmia

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
B6.129-Smn1/J

skeleton phenotype

decreased bone mineral content
- 6 month old mutants exhibit lower bone mineral content

decreased bone mineral density
- 6 month old mutants exhibit lower bone mineral density

The following phenotype relates to a compound genotype created using this strain

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
FVB.129(B6)-Smn1/J

skeleton phenotype

decreased bone mineral content
- 6 month old mutants exhibit lower bone mineral content

decreased bone mineral density
- 6 month old mutants exhibit lower bone mineral density

References

Osborne M; Gomez D; Feng Z; McEwen C; Beltran J; Cirillo K; El-Khodor B; Lin MY; Li Y; Knowlton WM; McKemy DD; Bogdanik L; Butts-Dehm K; Martens K; Davis C; Doty R; Wardwell K; Ghavami A; Kobayashi D; Ko CP; Ramboz S; Lutz C. 2012. Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models. Hum Mol Genet 21(20):4431-47PubMed: 22802075 MGI: J:186987

Additional - Smn1^{tm5(Smn1/SMN2)Mrph} related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Smn1
- Standard PCR:Smn1
- Standard PCR:Generic LacZ Melt Curve Analysis
- QPCR:Tg(SMN2*)
- Probe:Generic LacZ Probe
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as heterozygotes.
- Additional Breeding and Husbandry Support
Citation
When using the Smn1^C mouse strain in a publication, please cite the originating article(s) and include JAX stock #008604 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Smn1<tm5(Smn1/SMN2)Mrph>

Related Products and Services

Frozen Mouse Embryo	FVB.129(B6)-Smn1<tm5(Smn1/SMN2)Mrph>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	FVB.129(B6)-Smn1<tm5(Smn1/SMN2)Mrph>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	FVB.129(B6)-Smn1<tm5(Smn1/SMN2)Mrph>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	FVB.129(B6)-Smn1<tm5(Smn1/SMN2)Mrph>/J Frozen Embryo	$3373.50

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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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Also Known As:Smn1C

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Smn1tm5(Smn1/SMN2)Mrph

Allele Symbol: Smn1tm5(Smn1/SMN2)Mrph

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Smn1tm5(Smn1/SMN2)Mrph/Smn1+involves: 129S6/SvEvTac * C57BL/6NTac

mammalian phenotype

Genotype: Smn1tm5(Smn1/SMN2)Mrph/Smn1tm5(Smn1/SMN2)Mrphinvolves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

behavior/neurological phenotype

cellular phenotype

growth/size/body region phenotype

integument phenotype

limbs/digits/tail phenotype

muscle phenotype

nervous system phenotype

cardiovascular system phenotype

Genotype: Smn1tm5(Smn1/SMN2)Mrph/Smn1tm5(Smn1/SMN2)MrphB6.129-Smn1/J

skeleton phenotype

Genotype: Smn1tm5(Smn1/SMN2)Mrph/Smn1tm5(Smn1/SMN2)MrphFVB.129(B6)-Smn1/J

skeleton phenotype

References

Additional - Smn1tm5(Smn1/SMN2)Mrph related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Smn1^C

Smn1^{tm5(Smn1/SMN2)Mrph}

Allele Symbol: Smn1^{tm5(Smn1/SMN2)Mrph}

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1⁺
involves: 129S6/SvEvTac * C57BL/6NTac

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
B6.129-Smn1/J

Genotype: Smn1^{tm5(Smn1/SMN2)Mrph}/Smn1^{tm5(Smn1/SMN2)Mrph}
FVB.129(B6)-Smn1/J

Additional - Smn1^{tm5(Smn1/SMN2)Mrph} related