TY - JOUR
T1 - Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy
AU - Martinez, Tara L.
AU - Kong, Lingling
AU - Wang, Xueyong
AU - Osborne, Melissa A.
AU - Crowder, Melissa E.
AU - Van Meerbeke, James P.
AU - Xu, Xixi
AU - Davis, Crystal
AU - Wooley, Joe
AU - Goldhamer, David J.
AU - Lutz, Cathleen M.
AU - Rich, Mark M.
AU - Sumner, Charlotte J.
PY - 2012/6/20
Y1 - 2012/6/20
N2 - The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increasedSMNexpression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, butSMNmayhave variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.
AB - The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increasedSMNexpression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, butSMNmayhave variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.
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U2 - 10.1523/JNEUROSCI.0204-12.2012
DO - 10.1523/JNEUROSCI.0204-12.2012
M3 - Article
C2 - 22723710
AN - SCOPUS:84862883258
SN - 0270-6474
VL - 32
SP - 8703
EP - 8715
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 25
ER -