Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A.
Charcot-Marie-Tooth (CMT) disease type 2A is a progressive, neurodegenerative disorder affecting long peripheral motor and sensory nerves. The most common clinical sign is weakness in the lower legs and feet, associated with muscle atrophy and gait defects. The axonopathy in CMT2A is caused by mutations in Mitofusin 2 (Mfn2), a mitochondrial GTPase necessary for the fusion of mitochondria. Most Mfn2 disease alleles dominantly aggregate mitochondria upon expression in cultured fibroblasts and neurons. To determine whether this property is related to neuronal pathogenesis, we used the HB9 promoter to drive expression of a pathogenic allele, Mfn2(T105M), in the motor neurons of transgenic mice. Transgenic mice develop key clinical signs of CMT2A disease in a dosage-dependent manner. They have a severe gait defect due to an inability to dorsi-flex the hindpaws. Consequently, affected animals drag their hindpaws while walking and support themselves on the hind knuckles, rather than the soles. This distal muscle weakness is associated with reduced numbers of motor axons in the motor roots and severe reduction of the anterior calf muscles. Many motor neurons from affected animals show improper mitochondrial distribution, characterized by tight clusters of mitochondria within axons. This transgenic line recapitulates key motor features of CMT2A and provides a system to dissect the function of mitochondria in the axons of mammalian motor neurons.
Detmer
Scott A
SA
Division of Biology, California Institute of Technology, 1200 East California Boulevard, MC114-96, Pasadena, CA 91125, USA.
Vande Velde
Christine
C
Cleveland
Don W
DW
Chan
David C
DC
D000818:Animals; D001369:Axons / Q000473:pathology; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D017931:DNA Primers / Q000235:genetics; D020558:GTP Phosphohydrolases; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D007794:Lameness, Animal / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology; D009046:Motor Neurons / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human