title: Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.
abstract: Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization.
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Courchesne
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pazyra-Murphy
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lee
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype
chemical_list: C516947:Dync1h1 protein, mouse; D056445:Cytoplasmic Dyneins