Dynein is an essential motor protein required for the maintenance and survival of cells. Dynein forms a motor complex to carry intracellular cargoes like organelles, growth factors, peptides, and hormones along the microtubules inside the cells. In neurons, the dynein is the retrograde motor protein that moves cargoes from the neuronal tip to the neuronal soma along the length of an axon. Dynein has an established role in neuronal nuclear migration, transport of neuronal survival signals and growth factors, organelle positioning inside neurons etc. Hence, it is not very surprising that numerous mutations in dynein have been reported in association with neurodegenerative diseases in humans. The first human mutation (H306R) in dynein heavy chain was reported to cause Charcot-Marie-Tooth Type 2O disease (CMT2O) in humans. CMT2O patients display motor-sensory neuropathy symptoms such as muscle weaknesses and wasting in legs, skeletal deformities like pes cavus (high foot arching), difficulty in walking, and a loss of sensation. We developed a novel knock-in H304R mouse model with the corresponding CMT2O linked dynein mutation to understand the disease's molecular mechanism. We investigated and characterized the motor-sensory phenotype of the H304R mouse model (wildtype, heterozygous (H304R/+) and homozygous (H304R/R) mice). First, we started with testing mice on motor skills behavior tests such as tail suspension reflex, grip strength test, and rotarod test at 3, 6, 9 and 12 months of age. Both male and female groups of heterozygous (H304R/+) mice displayed mild defects in tail suspension reflex, grip strength, and rotarod performance. In contrast, homozygous (H304R/R) mice exhibited severe defects in the tail suspension reflex, grip strength, and rotarod performance right from an early age. Next, I analyzed the sensory phenotype of the H304R mouse model. Homozygous H304R/R mice appeared to have thinner sciatic nerves, reduced total fascicular area of the sciatic nerve, and significantly quicker latency to tail withdrawal from a pain stimulus than the wildtype and heterozygous H304R/+ mice. Collectively, our motor and sensory characterization studies reveal that H304R dynein mouse model recapitulates many of the phenotypes associated with CMT symptoms. Hence, the H304R model is a useful tool in understanding the dynein function in the onset and progression of CMT2O in humans.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Nandini, Swaran, "Motor and Sensory Characterization of a Mouse Model of Charcot-Marie-Tooth Type 2O Disease" (2019). Electronic Theses and Dissertations. 6386.