Overview

Also Known As:SMN2;Δ7;Cre-ER;Smn^Res , SMN2;Δ7;Cre-ER;Smn^COIN , Delta 7 mouse with hybrid rescue allele and tamoxifen inducible Cre

The severely affected "rescuable" SMA model mice, SMN2;Δ7;Cre-ER;Smn^Res/Res, allow tamoxifen-inducible rescue of Type II (moderate) proximal spinal muscular atrophy.

Donating Investigator

IMR Colony, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Tg(CAG-cre/Esr1*)5Amc

Allele Type
Transgenic (Recombinase-expressing, Inducible)

Tg(SMN2*delta7)4299Ahmb

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Grm7^{Tg(SMN2)89Ahmb}

Allele Type
Transgenic (Hypomorph, Inserted expressed sequence, Humanized sequence)

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), Humanized sequence, No functional change)	Smn1	survival motor neuron 1

Research Applications

Research Tools
Neurobiology Research
Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

These SMN2;Δ7;Cre-ER;Smn^Res mice harbor multiple mutations/transgenes.

The Smn rescue allele (Smn^Res; also called Smn1 conditional inversion or Smn1 COIN) is a functional null in the non-recombined state. Prior to Cre recombination, no full-length SMN transcript is detected in somatic tissue by RT-PCR. No spontaneous inversion of the allele is reported in the absence of Cre recombinase. The Smn^Res allele is designed to revert to a fully functional SMN upon exposure to Cre recombinase.

Mice homozygous for the Tg(SMN2)89 transgene (SMN2+/+), homozygous for the Tg(SMNΔ7)4299 transgene (SMNΔ7+/+), and homozygous for the Smn1^{tm3(SMN2/Smn1)Mrph} mutation (Smn^Res/Res) are a moderate Type II SMA mouse model with similar phenotype as Stock No. 005025. Those SMN2+/+;SMNΔ7+/+;Smn^Res/Res mice exhibit greatly reduced SMN protein in P4 spinal cord tissue, are born small with neuromuscular defects by 4-5 days old that progress to abnormal gait, hind limb weakness/immobility, and eventually death at approximately 13-17 days of age.

When also harboring a tamoxifen-inducible Cre recombinase (Cre-ER) under control of a ubiquitous promoter [Tg(CAG-CreER)5], mice with SMN2+/+;SMNΔ7+/+; Cre-ER+/-;Smn^Res/Res genotype are the severely affected "rescuable" SMA model (SMN2;Δ7;Cre-ER;Smn^Res/Res), and exhibit the same moderate Type II SMA phenotype in the absence of tamoxifen. Addition of tamoxifen results in widespread Cre recombinase expression and inversion of the Smn^Res allele to the "rescue" conformation. Specifically, Cre recombinase irreversibly inverts the fragment bordered by the lox71 and lox66 sites, and the resulting allele is "rescued" into a format that contains mouse Smn1 exons 1-7 and human SMN2 exon 8. Because the mouse Smn1 exon 7 is efficiently spliced, the majority of the mRNA from the Cre recombinase-induced rescue allele contains mouse Smn1 exon 7. When 4 day old SMN2+/+;SMNΔ7+/+;Cre-ER+/-;Smn^Res/Res mice are administered a single tamoxifen dose (75 mg/kg), they gradually gain strength, perform better in a righting reflex assay, and become significantly larger by 17 days old, and have significantly improved lifespan. Such improvements are progressively diminished when administering tamoxifen at later timepoints.

Mice heterozygous for the Smn1^{tm3(SMN2/Smn1)Mrph} mutation (Smn^Res/+) and homozygous for the other mutations/transgenes are viable and fertile with no reported abnormalities or symptoms of neuropathology. As such, The Jackson Laboratory Repository Stock No. 008783 is maintained as SMN2+/+;SMNΔ7+/+;Cre-ER+/-;Smn^Res/+. A researcher must breed SMN2+/+;SMNΔ7+/+;Cre-ER+/-;Smn^Res/+ mice together to generate the severely affected "rescuable" SMA model (SMN2;Δ7;Cre-ER;Smn^Res/Res).

Development

The SMN2;Δ7;Cre-ER;Smn^Res mice harbor several mutations/transgenes, as described below.

The creation of the Smn rescue allele (Smn^Res; also called Smn1 conditional inversion or Smn1 COIN) is described as Stock No. 007249. These mice were maintained upon mixed B6J;129 genetic background prior to being used for breeding as below.

The creation of the Tg(SMN2)89 transgene (SMN2) and Tg(SMNΔ7)4299 transgene (Δ7) are described for the moderate type II SMA mouse model; Stock No. 005025. Note the Tg(SMN2)89 transgene insertion site in on chromosome 6. These mice were bred to and maintained upon an FVB/N-congenic background prior to being used for breeding as below.

The creation of the tamoxifen-inducible ubiquitously expressed Cre transgene (Tg(CAG-CreER)5) is described as Stock No. 004682. These mice were bred to and maintained upon a C57BL/6J-congenic background prior to being used for breeding as below.

To generate the SMN2;Δ7;Cre-ER;Smn^Res animals, Smn^Res mice were bred to moderate type II SMA mice (Tg(SMN2)89;Smn1^+/-;Tg(SMNΔ7)4299). The SMN2;Δ7;Smn^Res/+ progeny (not retaining the Smn1^- knockout mutation) were identified, and then bred to Tg(CAG-CreER)5 mice. The resulting SMN2;Δ7;Cre-ER;Smn^Res/+ offspring (on a mixed C57BL/6;FVB/N;129 genetic background) were then bred together at The Jackson Laboratory Repository as Stock No. 008783.

The Jackson Laboratory Repository Stock No. 008783 colony is maintained as heterozygous for the Smn1^{tm3(SMN2/Smn1)Mrph} mutation (Smn^Res/+), homozygous for the Tg(SMNΔ7)4299 transgene (SMNΔ7+/+), homozygous for the Tg(SMN2)89 transgene (SMN2+/+), and hemizygous for the Tg(CAG-CreER)5 transgene (Cre-ER). That is, Smn^Res/+;SMNΔ7+/+;SMN2+/+;Cre-ER+/-. A researcher must breed Smn^Res/+;SMNΔ7+/+;SMN2+/+;Cre-ER+/- mice together to generate the severely affected "rescuable" SMA model (SMN2;Δ7;Cre-ER;Smn^Res/Res).

Expression Data

Expressed Gene	cre/Esr1, Cre recombinase and estrogen receptor 1 fusion gene,
Site of Expression	tamoxifen-inducible cre; widespread pattern of expression; tamoxifen administration will also induce Cre recombination in developing embryos of treated mothers and in cultured cells derived from transgenic mice
Expressed Gene	SMN2, survival of motor neuron 2, centromeric, human
Site of Expression	Tg(SMN2*delta7)4299Ahmb
Expressed Gene	SMN2, survival of motor neuron 2, centromeric, human
Site of Expression	Grm7^{Tg(SMN2)89Ahmb}
Site of Expression	Following Cre-mediated irreversible inversion of the fragment bordered by the lox71 and lox66 sites, the allele is "rescued" into a format that contains mouse Smn1 exons 1 through 7 and human SMN2 exon 8 and the resulting SMN protein is produced in motor neurons.

Control Suggestions

None Available

Additional Information

Considerations for Choosing Controls

Selected References

Lutz CM; Kariya S; Patruni S; Osborne MA; Liu D; Henderson CE; Li DK; Pellizzoni L; Rojas J; Valenzuela DM; Murphy AJ; Winberg ML; Monani UR. 2011. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest 121(8):3029-41PubMed: 21785219 MGI: J:176007

View All References

Genetics

Tg(CAG-cre/Esr1*)5Amc

Allele Symbol: Tg(CAG-cre/Esr1*)5Amc

Allele Name	transgene insertion 5, Andrew P McMahon
Allele Type	Transgenic (Recombinase-expressing, Inducible)
Allele Synonym(s)	transgene insertion 5, Andrew P McMahon; Tg(CAG-cre/Esr1*)5Amc
Gene Symbol and Name	Tg(CAG-cre/Esr1*)5Amc, transgene insertion 5, Andrew P McMahon
Gene Synonym(s)	CMV-creERT; CAG-CreERT2; CAGG-CreERT2; CAGGCre-ER^TM; CAGGCre-ERtm line 5.8; CAGGS-CreErT; Cre-ER; Cre-ERTM; ER-cre; Tg(CAG-cre/Esr1)5Amc; Tg(cre/Esr1)5Amc; Tg(CAG-cre/Esr1)5Amc; Tg(cre/Esr1)5Amc; CAGGS-CreER; CAGGCre-ER
Promoter	ACTB, actin, beta, chicken
Expressed Gene	cre/Esr1, Cre recombinase and estrogen receptor 1 fusion gene,
Site of Expression	tamoxifen-inducible cre; widespread pattern of expression; tamoxifen administration will also induce Cre recombination in developing embryos of treated mothers and in cultured cells derived from transgenic mice
Strain of Origin	(C57BL/6 x CBA)F1
Chromosome	UN
General Note	Homozygous transgenic mice are not viable or fertile. Hemizygous transgenic mice are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. In transgenic mice the mutant mouse estrogen receptor does not bind natural ligand at physiological concentrations but will bind the synthetic ligand, 4-hydroxytamoxifen. Restricted to the cytoplasm, the Cre/Esr1 fusion protein can only gain access to the nuclear compartment after exposure to tamoxifen. When crossed with a strain containing loxP sites flanking a sequence of interest, tamoxifen induced, Cre-mediated targeted deletions are generated in the offspring. Tamoxifen administration will induce Cre recombination in developing embryos of treated mothers and in cultured cells derived from transgenic mice. Note that this transgene does not contain the cre/ERT2 fusion but was mistakenly referred to by the synonym CAG-CreERT2 in publication. J:136965
Molecular Note	This transgene expresses a fusion protein consisting of Cre recombinase joined to the ligand-binding domain of a mouse estrogen receptor modified to bind to 4-hydroxytamoxifen, but not to endogenous estrogen. The CAG promoter, containing a chicken beta actin promoter/enhancer coupled with the cytomegalovirus immediate-early (CMV-IE) enhancer, drives high levels of expression in most tissues. In the presence of tamoxifen, the fusion protein is transported into the nucleus, where cre can excise loxP-flanked segments from conditionally modified genes.
Mutations Made By	Shigemi Hayashi, Columbia University

Tg(SMN2*delta7)4299Ahmb

Allele Symbol: Tg(SMN2*delta7)4299Ahmb

Allele Name	transgene insertion 4299, Arthur H M Burghes
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	Tg(SMN2*delta7)4299Ahmb; transgene insertion 4299, Arthur H M Burghes
Gene Symbol and Name	Tg(SMN2*delta7)4299Ahmb, transgene insertion 4299, Arthur H M Burghes
Gene Synonym(s)	Tg(SMN1*delta7)4299Ahmb; SMNdelta7
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

Grm7^{Tg(SMN2)89Ahmb}

Allele Symbol: Grm7^{Tg(SMN2)89Ahmb}

Allele Name	transgene insertion 89, Arthur H M Burghes
Allele Type	Transgenic (Hypomorph, Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	transgene insertion 89, Arthur H M Burghes; Grm7^{Tg(SMN2)89Ahmb}
Gene Symbol and Name	Grm7, glutamate receptor, metabotropic 7
Gene Synonym(s)	GPRC1G; E130018M02Rik; E130018M02Rik; Gpr1g; RIKEN cDNA 6330570A01 gene; Gpr1g; expressed sequence BB176677; MGLU7; mGlu7a receptor; MGLUR7; 6330570A01Rik; PPP1R87; GLUR7; 6330570A01Rik; BB176677; RIKEN cDNA E130018M02 gene; G protein-coupled receptor, family C, group 1, member G; mGluR7; Tg(SMN2)89Ahmb; SMN2
Promoter	SMN2, survival of motor neuron 2, centromeric, human
Expressed Gene	SMN2, survival of motor neuron 2, centromeric, human
Site of Expression	Grm7^{Tg(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

Smn1^{tm3(SMN2/Smn1)Mrph}

Allele Symbol: Smn1^{tm3(SMN2/Smn1)Mrph}

Allele Name	targeted mutation 3, Andrew Murphy
Allele Type	Targeted (Conditional ready (e.g. floxed), Humanized sequence, No functional change)
Allele Synonym(s)	targeted mutation 3, Andrew Murphy; Smn1^{tm3(SMN2/Smn1)Mrph}
Gene Symbol and Name	Smn1, survival motor neuron 1
Gene Synonym(s)	TDRD16A; BCD541; C-BCD541; T-BCD541; SMA2; AI849087; Smn; SMA@; SMA1; SMA3; SMN; SMNC; SMNT; GEMIN1; TDRD16B; SMA; SMA4; expressed sequence AI849087; survival motor neuron; Smn
Site of Expression	Following Cre-mediated irreversible inversion of the fragment bordered by the lox71 and lox66 sites, the allele is "rescued" into a format that contains mouse Smn1 exons 1 through 7 and human SMN2 exon 8 and the resulting SMN protein is produced in motor neurons.
Strain of Origin	(129S6/SvEvTac x C57BL/6NTac)F1
Chromosome	13
Molecular Note	Exons 7 and 8 of the mouse Smn1 (survival motor neuron 1) gene and a several hundred base pairs of flanking sequence were replaced with a fragment containing, in order: 1) an inverted lox71 site; 2) exon 7 from the human SMN2 (survival of motor neuron 2, centromeric) gene flanked by several hundred base pairs of intron sequence; 3) an inverted copy of mouse Smn1 exon 7 flanked by several hundred base pairs of intron sequence; 4) a lox66 site; 5) an FRT site remnant from a deleted selection cassette; and 6) human SMN2 exon 8 including the 3'UTR and polyA signal with several hundred base pairs of flanking sequence. The engineered allele expresses a hybrid Smn1 gene containing mouse Smn1 exons 1 through 6 and human SMN2 exons 7 and 8. The human SMN2 exon 7 is skipped in the majority of mRNA derived from the hybrid gene due to a single base pair difference in human SMN2 exon 7, compared to human SMN1 exon 7. Following Cre-mediated irreversible inversion of the fragment bordered by the lox71 and lox66 sites, the allele is "rescued" into a format that contains mouse Smn1 exons 1 through 7 and human SMN2 exon 8. Because the mouse Smn1 exon 8 is efficiently spliced, the majority of the mRNA from the rescue allele after Cre-mediated inversion contains mouse Smn1 exon 7.
Mutations Made By	Nicole Graiff, Regeneron

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Research Tools
- Cre-lox System
  - Cre Recombinase Expression: Germline/Embryonic Expression
  - Cre Recombinase Expression: Inducible
  - Cre Recombinase Expression
  - loxP-flanked Sequences
- Genetics Research
  - Mutagenesis and Transgenesis: Cre-lox System
- lacZ Expression
- Developmental Biology Research
  - Cre-lox System
- Neurobiology Research
Neurobiology Research
- Neurodevelopmental Defects
- Neuromuscular defects
- lacZ expression in neural tissue
- Neurodegeneration
- Ataxia (Movement) Defects
- Spinal Muscular Atrophy (SMA)
- Cre-lox System
  - loxP-flanked Sequences
  - Cre Recombinase expression in neural tissue
Developmental Biology Research
- Neurodevelopmental Defects

Mammalian Phenotype Terms by Genotype

References

Lutz CM; Kariya S; Patruni S; Osborne MA; Liu D; Henderson CE; Li DK; Pellizzoni L; Rojas J; Valenzuela DM; Murphy AJ; Winberg ML; Monani UR. 2011. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest 121(8):3029-41PubMed: 21785219 MGI: J:176007

Additional - Grm7^{Tg(SMN2)89Ahmb} related

Additional - Smn1^{tm3(SMN2/Smn1)Mrph} related

Additional - Tg(CAG-cre/Esr1*)5Amc related

Additional - Tg(SMN2*delta7)4299Ahmb related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Tg(CAG-cre)
- Probe:Generic Cre Probe
- Standard PCR:Generic Cre
- Standard PCR:Grm7
- Standard PCR:Tg(SMN2*)
- Standard PCR:Smn1
- Separated MCA:Smn1
- Standard PCR:Grm7 Alternate1
- Standard PCR:Generic Cre Melt Curve Analysis
- QPCR:Tg(SMN2*)
- Probe:Grm7-Probe
- Genotyping resources and troubleshooting
Breeding Considerations

Mice heterozygous for the Smn1^{tm3(SMN2/Smn1)Mrph} mutation (Smn^Res/+) and homozygous for the other mutations/transgenes are viable and fertile with no reported abnormalities or symptoms of neuropathology. As such, The Jackson Laboratory Repository Stock No. 008783 is maintained as heterozygous for the Smn1^{tm3(SMN2/Smn1)Mrph} mutation (Smn^Res/+), homozygous for the Tg(SMNΔ7)4299 transgene (SMNΔ7+/+), homozygous for the Tg(SMN2)89 transgene (SMN2+/+), and hemizygous for the Tg(CAG-CreER)5 transgene (Cre-ER). That is, Smn^Res/+;SMNΔ7+/+;SMN2+/+;Cre-ER+/-. A researcher must breed Smn^Res/+;SMNΔ7+/+;SMN2+/+;Cre-ER+/- mice together to generate the severely affected "rescuable" SMA model (SMN2;Δ7;Cre-ER;Smn^Res/Res).
- Additional Breeding and Husbandry Support
Citation
When using the SMN2;Δ7;Cre-ER;Smn^Res , SMN2;Δ7;Cre-ER;Smn^COIN , Delta 7 mouse with hybrid rescue allele and tamoxifen inducible Cre mouse strain in a publication, please cite the originating article(s) and include JAX stock #008783 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

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Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Hemizygous or Non carrier for Tg(CAG-cre/Esr1)5Amc, Heterozygous or wildtype for Smn1<tm3(SMN2/Smn1)Mrph> Hemizygous for Tg(SMN2delta7)4299Ahmb Homozygous for Tg(SMN2)89Ahmb

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Also Known As:SMN2;Δ7;Cre-ER;SmnRes , SMN2;Δ7;Cre-ER;SmnCOIN , Delta 7 mouse with hybrid rescue allele and tamoxifen inducible Cre

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(CAG-cre/Esr1*)5Amc

Allele Symbol: Tg(CAG-cre/Esr1*)5Amc

Tg(SMN2*delta7)4299Ahmb

Allele Symbol: Tg(SMN2*delta7)4299Ahmb

Grm7Tg(SMN2)89Ahmb

Allele Symbol: Grm7Tg(SMN2)89Ahmb

Smn1tm3(SMN2/Smn1)Mrph

Allele Symbol: Smn1tm3(SMN2/Smn1)Mrph

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

References

Additional - Grm7Tg(SMN2)89Ahmb related

Additional - Smn1tm3(SMN2/Smn1)Mrph related

Additional - Tg(CAG-cre/Esr1*)5Amc related

Additional - Tg(SMN2*delta7)4299Ahmb 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

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:SMN2;Δ7;Cre-ER;Smn^Res , SMN2;Δ7;Cre-ER;Smn^COIN , Delta 7 mouse with hybrid rescue allele and tamoxifen inducible Cre

Grm7^{Tg(SMN2)89Ahmb}

Allele Symbol: Grm7^{Tg(SMN2)89Ahmb}

Smn1^{tm3(SMN2/Smn1)Mrph}

Allele Symbol: Smn1^{tm3(SMN2/Smn1)Mrph}

Additional - Grm7^{Tg(SMN2)89Ahmb} related

Additional - Smn1^{tm3(SMN2/Smn1)Mrph} related