You are here

UCF Digital Collections ยป ETD Collection

Motor and sensory characterization of a mouse model of Charcot-Marie-Tooth type 2O disease

Download pdf | Full Screen View

Date Issued:
2019
Abstract/Description:
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.
Title: Motor and sensory characterization of a mouse model of Charcot-Marie-Tooth type 2O disease.
54 views
26 downloads
Name(s): Nandini, Swaran, Author
King, Stephen, Committee Chair
Kim, Yoon-Seong, Committee Member
Estevez, Alvaro, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2019
Publisher: University of Central Florida
Language(s): English
Abstract/Description: 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.
Identifier: CFE0007508 (IID), ucf:52651 (fedora)
Note(s): 2019-05-01
Ph.D.
Medicine, Burnett School of Biomedical Sciences
Doctoral
This record was generated from author submitted information.
Subject(s): Dynein mouse CMT
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0007508
Restrictions on Access: campus 2020-05-15
Host Institution: UCF

In Collections