STOCK Grm7^{Tg(SMN2)89Ahmb} Smn1^tm1Msd Tg(Prnp-SMN)92Ahmb/J

Stock number: 008212
Research areas: Developmental Biology Research, Neurobiology Research, Research Tools

Description

These SMN2; Smn; PrP92-SMN mutant mice may be useful in neuromuscular studies including spinal muscular atrophy (SMA).

Detailed description

As described for SMA mice (see Stock No. 005024), mice homozygous for Smn1^tm1Msd targeted mutation (Smn null allele) and human SMN2 transgene (SMN2 low copy line 89) exhibit symptoms, neuropathology, and early lethality similar to human type I proximal spinal muscular atrophy (SMA) patients. As an addition to that SMA model, this strain also carries the PrP-SMN transgene; with the mouse prion protein (PrP or Prnp) promoter directing full-length human SMN expression at high levels in neurons (with low expression in skeletal muscle and liver). When the PrP-SMN transgene is derived from PrP92-SMN founder mice, high SMN expression in spinal cord and brain is observed. Homozygous SMN2; Smn; Prp92-SMN mice are rescued from the severe SMA phenotype, have significantly increased lifespan (average of 210 days) and have normal lumbar motor neuron root counts. Homozygous SMN2; Smn; PrP92-SMN males are infertile, females are fertile but poor mothers, and both sexes exhibit necrotic tail development with about one-third of the normal length remaining around the time of weaning. These SMN2; Smn; PrP92-SMN mutant mice may be useful in neuromuscular studies including spinal muscular atrophy (SMA).

Development

These SMN2; Smn; PrP92-SMN mutant mice harbor a targeted mutation and two trangenes, all independently created.

The Smn1^tm1Msd targeted mutation was created in the laboratory of Dr. Michael Sendtner at the University of Wurzburg, Germany. Exon 2 of the targeted gene was disrupted with a neomycin cassette and a lacZ gene (fused to the first 40 nucleotides of the disrupted exon to permit expression of the lacZ gene in tissues where Smn is normally expressed). The construct was electroporated into 129P2/OlaHsd-derived E14Tg2a-IV embryonic stem (ES) cells. Chimeric animals were crossed to C57BL/6 for an unspecified number of generations.

The PrP-SMN transgene was designed with the mouse prion protein gene (PrP or Prnp) promoter region and exon 1 and 2, full-length SMN cDNA (containing exons 1-8), and two SV40 polyA signals. This transgene was microinjected into fertilized FVB/N oocytes. Mice from founder line 92 (PrP92-SMN) were found to have 8-9 copies of the transgene.

The SMN2 transgene was created in the laboratory of Dr. Arthur Burghes at The Ohio State University. A 35.5 kb BamHI genomic fragment encoding the human SMN2 promoter and gene (derived from genomic clone PAC215P15) was injected into fertilized FVB/N mouse oocytes and founder animals obtained. Transgenic SMN2 mice from founder line 89 were established and found to contain one copy of the transgene (also called SMN2 low copy line 89).

These SMN2; Smn; PrP92-SMN mutant mice (heterozygous for the targeted mutation and homozygous for both transgenes) were maintained on a mixed genetic background (mostly FVB/N and C57BL/6) for many generations prior to arrival at The Jackson Laboratory.

Allele

Symbol: Tg(Prnp-SMN)92Ahmb
Name: transgene insertion 92, Arthur H M Burghes
MGI accession ID: MGI:3774945
Generation method: Transgenic
Attributes: Inserted expressed sequence
Marker symbol: Tg(Prnp-SMN)92Ahmb
Marker name: transgene insertion 92, Arthur H M Burghes
Chromosome: UN
Strain of origin: FVB/N
Expressed genes: SMN1,survival of motor neuron 1, telomeric,human
Site of expression: The expression of the lacZ gene in tissues where Smn is normally expressed was noted.
Molecular note: The PrP-SMN transgene was designed with the mouse prion protein gene (PrP or Prnp) promoter region and exon 1 and 2, full-length SMN cDNA (containing exons 1-8), and two SV40 polyA signals. Mice from founder line 92 (PrP92-SMN) were found to have 8-9 copies of the transgene.

Allele

Symbol: Smn1^tm1Msd
Name: targeted mutation 1, Michael Sendtner
MGI accession ID: MGI:2183946
Generation method: Targeted
Attributes: Reporter; Null/Knockout
Marker symbol: Smn1
Marker name: survival motor neuron 1
Chromosome: 13
Strain of origin: 129P2/OlaHsd
Expressed genes: lacZ,beta-galactosidase,E. coli
Site of expression: The expression of the lacZ gene in tissues where Smn is normally expressed was noted.
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.

Allele

Symbol: Grm7^{Tg(SMN2)89Ahmb}
Name: transgene insertion 89, Arthur H M Burghes
MGI accession ID: MGI:2448989
Generation method: Transgenic
Attributes: Hypomorph; Inserted expressed sequence; Humanized sequence
Marker symbol: Grm7
Marker name: glutamate receptor, metabotropic 7
Chromosome: 6
Strain of origin: FVB/N
Expressed genes: SMN2,survival of motor neuron 2, centromeric,human
Site of expression: Human SMN2 protein is expressed in the tissues examined (brain, liver, spinal cord) [Stock No. 005024].
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.