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Human Molecular Genetics, 2002, Vol. 11, No. 12 1439-1447
© 2002 Oxford University Press

Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model

Carmen Cifuentes-Diaz, Sophie Nicole, Maria E. Velasco, Christophe Borra-Cebrian, Cristina Panozzo, Tony Frugier, Gaelle Millet, Natacha Roblot, Vandana Joshi and Judith Melki*

Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Evry, EMI-9913, GENOPOLE, 91057 Evry, France

Received February 7, 2002; Accepted March 27, 2002

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.

* To whom correspondence should be addressed at: Molecular Neurogenetics Laboratory, INSERM, Université d'Evry, EMI-9913, GENOPOLE, 2 rue Gaston Crémieux, CP5724, 91057 Evry, France. Tel: +33 1 6087 4552; Fax: +33 1 6087 4550; Email: j.melki{at}genopole.inserm.fr


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