Effect of genetic background on the phenotype of the Smn2B/- mouse model of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is caused by mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene in humans. Modifiers of the SMA symptoms have been identified and genetic background has a substantial effect in the phenotype and survival of the severe mouse model of SMA. Previously, we generated the less severe Smn2B/- mice on a mixed genetic background. To assess the phenotype of Smn deficiency on a pure genetic background, we produced Smn2B/2B congenic mice on either the C57BL/6 (BL6) or FVB strain background and characterized them at the 6th generation by breeding to Smn+/- mice. Smn2B/- mice from these crosses were evaluated for growth, survival, muscle atrophy, motor neuron loss, motor behaviour, and neuromuscular junction pathology. FVB Smn2B/- mice had a shorter life span than BL6 Smn2B/- mice (median of 19 days vs. 25 days). Similarly, all other defects assessed occurred at earlier stages in FVB Smn2B/-mice when compared to BL6 Smn2B/-mice. However, there were no differences in Smn protein levels in the spinal cords of these mice. Interestingly, levels of Plastin 3, a putative modifier of SMA, were significantly induced in spinal cords of BL6 Smn2B/- mice but not of FVB Smn2B/-mice. Our studies demonstrate that the phenotype in Smn2B/-mice is more severe in the FVB background than in the BL6 background, which could potentially be explained by the differential induction of genetic modifiers.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada|University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario, Canada|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
Mehdi
M
Eshraghi
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada|University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario, Canada|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
Emily
E
McFall
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada|University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario, Canada|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
Sabrina
S
Gibeault
Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
Rashmi
R
Kothary
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D000068617:Genetic Background; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009046:Motor Neurons; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction; D010641:Phenotype; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein