Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here new SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor defects and developmental breathing disorders reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of neuromuscular junction defects in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating new therapeutics.
Michaud
Magali
M
Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprise, Case 931, 13288 Marseille, France.
Arnoux
Thomas
T
Bielli
Serena
S
Durand
Estelle
E
Rotrou
Yann
Y
Jablonka
Sibylle
S
Robert
Fabrice
F
Giraudon-Paoli
Marc
M
Riessland
Markus
M
Mattei
Marie-Geneviève
MG
Andriambeloson
Emile
E
Wirth
Brunhilde
B
Sendtner
Michael
M
Gallego
Jorge
J
Pruss
Rebecca M
RM
Bordet
Thierry
T
D000818:Animals; D003964:Diaphragm / Q000294:innervation / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005804:Genes, Lethal / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020511:Neuromuscular Junction Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012133:Respiratory Paralysis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein