Strain Name:
STOCK Grm7Tg(SMN2)89Ahmb Smn1tm1Msd Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch/Mmjax
Stock Number:
041843-JAX
Citation ID:
RRID:MMRRC_041843-JAX
Other Names:
SMA/U7, SMN2+/+;Smn-/-;U7-ESE-B+

Gene Information

Smn1tm1Msd
Name: survival motor neuron 1; targeted mutation 1, Michael Sendtner
Synonyms: SMN-
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 13
Alteration at locus: Knockout
Smn1
Name: survival motor neuron 1
Synonyms: SMN
Type: Gene
Species: Mus musculus (mouse)
Chromosome: 13
Alteration at locus: Knockout
NCBI: 20595
Homologene: 292
Grm7Tg(SMN2)89Ahmb
Name: transgene insertion 89, Arthur H M Burghes
Synonyms: Tg(SMN2)89Ahmb, SMN2
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 6
Alteration at locus: Transgenic
Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch
Name: transgene insertion 4, Daniel Schuemperli
Synonyms: U7-ESE-B
Type: Allele
Species: Mus musculus (mouse)
Chromosome: unknown
Alteration at locus: Transgenic
EGFP
Name: enhanced green fluorescent protein
Type: Gene
Species: Aequorea victoria (jellyfish)
Alteration at locus: Transgenic
Grm7
Name: glutamate receptor, metabotropic 7
Synonyms: mGluR7, Gpr1g, E130018M02Rik, 6330570A01Rik, mGlu7a receptor
Type: Gene
Species: Mus musculus (mouse)
Chromosome: 6
Alteration at locus: Transgenic
NCBI: 108073
HGNC: HGNC:4599
Homologene: 20233
SMN2
Name: survival of motor neuron 2, centromeric
Type: Gene
Species: Homo sapiens (human)
Chromosome: 5
Alteration at locus: Transgenic
Rnu7
Name: U7 small nuclear RNA
Type: Gene
Species: Mus musculus (mouse)
Chromosome: 6
Alteration at locus: Transgenic
NCBI: 19866
VEGA: 6
PGK1
Name: phosphoglycerate kinase 1
Type: Gene
Species: Homo sapiens (human)
Chromosome: X
Alteration at locus: Transgenic
Genetic Alterations

Smn1tm1Msd A lacZ-neo cassette was inserted into exon 2 by homologous recombination resulting in an in-frame fusion of lacZ to exon 2.

Grm7Tg(SMN2)89Ahmb 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.

Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch The U7-ESE-B transgenic mice were created using a lentiviral transgenic approach. The U7-ESE-B splicing correction cassette encodes a tailed antisense oligonucleotide directed to the 3' part of human SMN2 exon 7 and an additional splicing enhancer sequence. To create this cassette, a 570-bp region of the U7 murine wild-type gene (Rnu7) was obtained containing 341-bp 5'-flanking sequence (including the distal and proximal sequence promoter elements [DSE and PSE]), 62-bp U7 snRNA coding region and 167-bp 3' sequence (including the 3' box). Next, several in vitro modifications were made within the U7 snRNA coding region. The resulting U7-ESE-B splicing correction cassette was introduced into the third generation (self-inactivating) lentiviral vector pRRL-SIN-cPPT-hPGK-GFP-WPRE. The resulting ~4.4-kbp transgene had U7-ESE-B inserted upstream of the hPGK promoter and in sense orientation with EGFP. Lentiviral transgenesis was performed by perivitelline injection into B6D2G1 (derived from C57BL/6J x DBA/2J mice) fertilized oocytes.


Genotype Determination
Phenotype

The Grm7Tg(SMN2)89Ahmb transgene expresses the entire human SMN2 gene driven by its own promoter, whereas no endogenous Smn1 expression is observed due to the Smn1tm1Msd allele. Mice on FVB/NJ genetic background and homozygous for Grm7Tg(SMN2)89Ahmb and Smn1tm1Msd model severe type I SMA, exhibiting neuropathology and early lethality (4-7 days) similar to human type I SMA patients.

The Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch transgene copy number is variable, and triple mutant mice with higher Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch copy number show greater phenotype rescue. Mice with ~one Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch transgene copy survive up to 3 weeks. Mice with ~five Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch copies exhibit life extension to more than one year, and almost complete recovery of muscle functions and other disease parameters. EGFP fluorescence is observed in blood samples.

The donating investigator reported that a mixed background (FVB/N, C57BL/6J, and DBA/2J) generally results in a more severe SMA phenotype when compared to mice of the same genotype on an FVB genetic background.

Mammalian Phenotype Terms
Allelic Composition: (Genetic Background: )

MeSH Terms
  • Animals
  • Base Sequence
  • Exons
  • Genetic Therapy
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy, Spinal/metabolism
  • Muscular Atrophy, Spinal/therapy
  • RNA Splicing
  • RNA, Small Nuclear/genetics
  • RNA, Small Nuclear/therapeutic use
  • Survival of Motor Neuron 2 Protein/genetics
  • Survival of Motor Neuron 2 Protein/metabolism
  • Amino Acid Sequence
  • Cell Death/genetics
  • Cyclic AMP Response Element-Binding Protein
  • Embryonic and Fetal Development/genetics
  • Gene Expression Regulation, Developmental
  • Mice, Knockout
  • Motor Neurons/pathology
  • Nerve Tissue Proteins/genetics
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • Animals, Newborn
  • Blotting, Northern
  • Blotting, Western
  • Brain Stem/metabolism
  • Brain Stem/pathology
  • Centromere
  • Disease Models, Animal
  • Gene Dosage
  • Genotype
  • In Vitro Techniques
  • Microinjections
  • Muscular Atrophy, Spinal/mortality
  • Muscular Atrophy, Spinal/pathology
  • Nerve Tissue Proteins/metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord/metabolism
  • Spinal Cord/pathology
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Diaphragm/pathology
  • Diaphragm/ultrastructure
  • Microscopy, Electron, Transmission
  • Mitochondria/diagnostic imaging
  • Mitochondria/pathology
  • Motor Neurons/ultrastructure
  • Muscle, Skeletal/diagnostic imaging
  • Muscle, Skeletal/pathology
  • Neuromuscular Junction/genetics
  • Neuromuscular Junction/pathology
  • Neuromuscular Junction/ultrastructure
  • Ultrasonography
Strain Development

Mice carrying the Smn1tm1Msd and Grm7Tg(SMN2)89Ahmb alleles were maintained on an FVB/NJ background.

Founder female epfl-4 (brown coat color and 27.8 transgene copy number) carrying the Tg(Rnu7*-SMN2,PGK1-EGFP)4Dasch allele was bred to a male carrying the Smn1tm1Msd and Grm7Tg(SMN2)89Ahmb alleles to generate triple-mutant germline carriers.

The triple-mutant colony was maintained by breeding mice homozygous for Grm7Tg(SMN2)89Ahmb, heterozygous for the Smn1tm1Msd null allele and hemi or homozygous for Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch together for more than 15 generations.

The donating investigator reported U7-ESE-B transgene copy number is variable, selected breeders with higher copy number and suggests at least some of the transgene copies are linked. Mice with approximately eight copies of Tg(Rnu7-SMN2*,PGK1-EGFP)4Dasch were donated.

Suggested Control Mice
Wild-type littermates
  • Developmental Biology
  • Models for Human Disease
  • Neurobiology
Donor
Daniel Schuemperli, Ph.D., Universitaet Bern.
Arthur H.M. Burghes, Ph.D., Ohio State University, Wexner Medical Center.
Michael Sendtner, Ph.D., Universitaet Wuerzburg.
Primary Reference

Meyer K, Marquis J, Trub J, Nlend Nlend R, Verp S, Ruepp MD, Imboden H, Trono D, Schumperli D. Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation. Hum Mol Genet. 2009 Feb 1;18(3):546-55. Epub 2008 Nov 13. (Medline PMID: 19010792)

Schrank B, Götz R, Gunnersen JM, Ure JM, Toyka KV, Smith AG, Sendtner M. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9920-5. (Medline PMID: 9275227)

Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S,Schrank B, Rossoll W, Prior TW, Morris GE, Burghes AH. The human centromericsurvival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) miceand results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000 Feb12;9(3):333-9. Erratum in: Hum Mol Genet. 2007 Nov 1;16(21):2648. Rossol, W[corrected to Rossoll, W]. (Medline PMID: 10655541)

Voigt T, Meyer K, Baum O, Schümperli D. Ultrastructural changes in diaphragmneuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy andtheir prevention by bifunctional U7 snRNA correcting SMN2 splicing. NeuromusculDisord. 2010 Nov;20(11):744-52. doi: 10.1016/j.nmd.2010.06.010. Epub 2010 Sep 15.(Medline PMID: 20832308)

Colony and Husbandry Information

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email csmmrrc@jax.org .
Overall Breeding Performance
Good
NOTE: "Hemizygote" as used here refers to males carrying a mutation on the X Chromosome or mice of either sex carrying an inserted transgene with no homologous allele on the other chromosome.
Viability and Fertility: Female Male Comments
Homozygotes are viable: Undetermined Undetermined
Homozygotes are fertile: Undetermined Undetermined
Hetero/Hemizygotes are fertile: Undetermined Undetermined
Age Reproductive Decline: Undetermined Undetermined
Recommended wean age
3-4 weeks

Order Request Information

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Cryopreserved material may be available upon request, please inquire to csmmrrc@jax.org for more information.

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # Description Distribution Fee / Unit (US $) Units Notes
041843-JAX-SPERM Cryo-preserved spermatozoa $437.00 / $437.00
Non-Profit / For-Profit
Aliquot Approximate quantity3
041843-JAX-RESUS Litter recovered from cryo-archive $2,022.00 / $2,022.00
Non-Profit / For-Profit
Litter Recovered litter4; additional fees for any special requests.
Cryopreserved material may be available upon request, please inquire to csmmrrc@jax.org for more information.

1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.