title: Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.
abstract: Smn+/-transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back.
  
  
  
  Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn+/-transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn+/-transgenic mouse increases their susceptibility to cell death demonstrated that all the motoneurons survived and they sustained their capacity to regenerate their nerve fibres. It is concluded the systematic die-back of motoneurons that innervate both fast- and slow-twitch muscle fibres is not related to immaturity of the neuromuscular system in SMA.
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.|Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Udina
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.|Exercise Biochemistry Laboratory, Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada, T6G 2H9.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Putman
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.|Exercise Biochemistry Laboratory, Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada, T6G 2H9.
authors.forename: Luke R
authors.identifier: 0000-0001-6771-1200
authors.initials: LR
authors.lastname: Harris
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.
authors.forename: Neil
authors.initials: N
authors.lastname: Tyreman
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.|Exercise Biochemistry Laboratory, Faculty of Physical Education and Recreation, University of Alberta, Edmonton, AB, Canada, T6G 2H9.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Cook
authors.affiliation: Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.|Division of Rehabilitation and Physical Medicine of the Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G 2S2.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D005267:Femoral Nerve / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000503:physiopathology*; D012584:Sciatic Nerve / Q000502:physiology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000502:physiology
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein
keywords: Smn+/− III transgenic mice; motoneuron counts; motor units; spinal muscular atrophy