Phenotypic analysis of rumpshaker mutation on two different genetic backgrounds

Al-Saktawi, Khalid A (2002) Phenotypic analysis of rumpshaker mutation on two different genetic backgrounds. PhD thesis, University of Glasgow.

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rumpshaker (rsh) is a recessive X-linked point mutation (Ile186Thr) which produces dysmyehnation in the murine central nervous system. This study compared the behavioural and pathological aspects of the mutation on the C57BL/6 background (C57 rsh) to those on the C3H background (C3H rsh). C3H rsh is more mildly affected behaviourally and pathologically than C57 rsh. C3H rsh has normal longevity and is also able to reproduce successfully. In contrast, C57 rsh develops seizures at about postnatal day (P25) and dies between 4-5 weeks. Both C3H rsh and C57 rsh fail to myelinate properly and develop dysmyelination in the CNS with the C57 rsh being more severely affected. This feature coincides with stages of active myelinogenesis. Western blot analyses strongly supports this finding as the levels of major myelin proteins are considerably reduced in the C57 rsh compared with C3H rsh. There are significant differences between the mutants and their normal littermates on both genetic backgrounds and between the two mutants themselves. The total glial density is notably increased in the C57 rsh which is coupled with an increase in dead cells in the cervical spinal cord white matter. In vivo BrdU labelling shows that proliferation rates and the number of dividing cells are markedly greater in the C57 rsh. In spite of the differences between the two strains, C3H rsh and C57 rsh both maintain the numbers of oligodendrocytes. Nonetheless, the activated macrophage/microglial cells are more marked in C57 rsh CNS white matter than C3H rsh. Surprisingly, the actual number of astrocytes remained unchanged, however, their activation is represnted by an increase in GFAP, as shown by immunostaining and western immunoblotting. This study suggests that there is no direct causal link between the dysmyelination and the oligodendrocyte number or even the death of oligodendrocye lineages. However, it provides evidence to support the notion that the severity of the disease correlates with the number of apoptotic cells, the reduced amount of myelin and the activation of microglia/macrophages. While the rsh mutation on either genetic background is similarly heritable, the differences in phenotypes are likely attributable to differences in genetic background, thus suggesting the importance of modifying loci in determining the phenotype.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Ian Griffiths
Keywords: Genetics
Date of Award: 2002
Depositing User: Enlighten Team
Unique ID: glathesis:2002-71964
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 13:37
Last Modified: 17 May 2019 13:37

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