The Effect of Genetic Background on Charcot-Marie-Tooth Histopathology in Mice

Lily Moy

Document Type

Article

Publication Date

Summer 2023

Keywords

JMG

JAX Location

In: Student Reports, Summer 2023, The Jackson Laboratory

Abstract

Nerve histology from genetically diverse mice may help us determine if strain background influences disease severity of Charcot-Marie Tooth Disease type 2D (CMT2D). Quantitatively assessing disease phenotype variability in genetically diverse mice enables us to identify alleles associated with susceptibility and resilience (Saul, 2019). We are applying this method to CMT2D, assessing variation in nerve histology using metrics such as axon number, axon diameter and myelin thickness. Gars-delETAQ mice were crossed with DO founder mice to obtain the Gars-delETAQ x DO founder F1s, which exhibit disease phenotypes. The cross section of motor and sensory femoral nerves from 200 mice was imaged using light microscopy and a smaller subset was analyzed to find axon number, G-ratio, and other histological features, which allowed us to assess the performance of emerging automated analysis tools. Most Gars-delETAQ x DO founder strains exhibited varying levels of axon shrinkage, loss of body mass, and decreased nerve conduction velocities and muscle endurance, validating that genetic background does affect CMT2D phenotypes. Interestingly, the PWK/PhJ strain showed a proportional decrease in both axons and myelin thickness. The NOD/ShiLtJ strain had an opposite effect due to an overall decrease in axon diameter and an increase in thickly-myelinated small axons, making for a significantly smaller G-ratio than any other strain. 129S1/SvlmJ was the only strain to exhibit a significant decrease in axon count in addition to showing the lowest wire hang duration, nerve conduction velocity, and muscle to body weight ratio of any strain. Using the 2-way ANOVA tests and simple linear regression models, many strains did not show a significant change in G-ratio across strains, but consistently significantly decreased between WT and ETAQ within the strain. Axon counts were not significantly different in most tests, but typically decreased when WT and ETAQ are compared. Axon diameters differed in less than half of the founder strains, but always differed between WT and ETAQ within the strain.

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