Register New MMRRC Account
Reset Password
Register for New Mouse Models
Click Here for Additional Contact Information
Availability & Fees Order this Strain
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.
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.
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.
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)
Cryo-recovered strains distributed by the MMRRC at JAX are shipped to the customer from the Pathogen & Opportunistic-Free Animal Room G200 - see https://www.jax.org/jax-mice-and-services/customer-support/customer-service/animal-health/health-status-reports.
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.
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.