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

Stock number: 008604
Product name: Smn1^C
Research areas: Neurobiology Research

Description

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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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.

Allele

Symbol: Smn1^{tm5(Smn1/SMN2)Mrph}
Name: targeted mutation 5, Andrew Murphy
MGI accession ID: MGI:3794202
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: Smn allele C
Marker symbol: Smn1
Marker name: survival motor neuron 1
Marker synonyms: BCD541; C-BCD541; GEMIN1; SMA; SMA@; SMA1; SMA2; SMA3; SMA4; Smn; SMNC; SMNT; T-BCD541; TDRD16A; TDRD16B
Chromosome: 13
Strain of origin: (129S6/SvEvTac x C57BL/6NTac)F1
Expressed genes: Smn1,survival motor neuron 1,mouse, laboratory; SMN2,survival of motor neuron 2, centromeric,human
Site of expression: Smn1 is normally expressed in motor neurons, particularly in the spinal chord.
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.