title: Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model.
abstract: Mutations of survival of the motor neuron gene (SMN1) are responsible for spinal muscular atrophy (SMA), a common genetic cause of death in childhood. The cellular mechanism by which mutations of SMN1 are responsible for the selective neuromuscular defect and motor neuron cell degeneration observed in SMA has not been described. We have previously generated mice carrying a homozygous deletion of Smn exon 7 directed to neurons. We report here that these mutant mice display a dramatic and progressive loss of motor axons involving both proximal and terminal regions, in agreement with the skeletal muscle denervation process and disease progression. Moreover, we found massive accumulation of neurofilaments, including phosphorylated forms, in terminal axons of the remaining neuromuscular junctions. This aberrant cytoskeletal organization of synaptic terminals was associated with reduction of branched structures of the postsynaptic apparatus and defect of axonal sprouting in mutant mice. Together, these findings may be responsible for severe motor neuron dysfunction, and suggest that loss of motor neuron cell bodies results from a 'dying-back' axonopathy in SMA. Smn mutant mice should represent a valuable model for elucidating the pathway linking Smn to cytoskeletal organization.
authors.affiliation: Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Evry, EMI-9913, GENOPOLE, 91057 Evry, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cifuentes-Diaz
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.forename: Maria E
authors.initials: ME
authors.lastname: Velasco
authors.forename: Christophe
authors.initials: C
authors.lastname: Borra-Cebrian
authors.forename: Cristina
authors.initials: C
authors.lastname: Panozzo
authors.forename: Tony
authors.initials: T
authors.lastname: Frugier
authors.forename: Gaelle
authors.initials: G
authors.lastname: Millet
authors.forename: Natacha
authors.initials: N
authors.lastname: Roblot
authors.forename: Vandana
authors.initials: V
authors.lastname: Joshi
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein; D051379:Mice; D009045:Motor Endplate / Q000378:metabolism* / Q000648:ultrastructure; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein