title: Defective neuromuscular junction organization and postnatal myogenesis in mice with severe spinal muscular atrophy.
abstract: A detailed pathologic analysis was performed on Smn(-/-);SMN2 mice as a mouse model for human type I spinal muscular atrophy (SMA). We provide new data concerning changes in the spinal cord, neuromuscular junctions and muscle cells, and in the organs of the immune system. The expression of 10 synaptic proteins was analyzed in 3-dimensionally reconstructed neuromuscular junctions by confocal microscopy. In addition to defects in postsynaptic occupancy, there was a marked reduction in calcitonin gene-related peptide and Rab3A in the presynaptic motor terminals of some, but not all, of the skeletal muscles analyzed. Defects in the organization of presynaptic nerve terminals were also detected by electron microscopy. Moreover, degenerative changes in muscle cells, defective postnatal muscle growth, and prominent muscle satellite cell apoptosis were also observed. All of these changes occurred in the absence of massive loss of spinal cord motoneurons. On the other hand, astroglia, but not microglia, increased in the ventral horn of newborn SMA mice. In skeletal muscles, the density of interstitial macrophages was significantly reduced, and monocyte chemotactic protein-1 was downregulated. These findings raise questions regarding the primary contribution of a muscle cell defect to the SMA phenotype.
authors.affiliation: Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Dachs
authors.forename: Marta
authors.initials: M
authors.lastname: Hereu
authors.forename: Lídia
authors.initials: L
authors.lastname: Piedrafita
authors.forename: Anna
authors.initials: A
authors.lastname: Casanovas
authors.forename: Jordi
authors.initials: J
authors.lastname: Calderó
authors.forename: Josep E
authors.initials: JE
authors.lastname: Esquerda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000254:growth & development / Q000473:pathology* / Q000648:ultrastructure; D020511:Neuromuscular Junction Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism
chemical_list: C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D020692:rab3 GTP-Binding Proteins; D015740:Calcitonin Gene-Related Peptide