Phenotypic Analysis of the Plp-Deficient Mouse

Yool, Donald Andrew (2000) Phenotypic Analysis of the Plp-Deficient Mouse. PhD thesis, University of Glasgow.

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Abstract

The myelin proteolipid protein (Plp) gene encodes the major protein components of compact central nervous system myelin. Mutations of this gene lead to severe dysmyelinating disease and oligodendrocyte death suggesting roles for Plp gene products as vital structural components of compact myelin and as oligodendrocyte maturation or survival factors. The Plp gene knockout mouse was generated (Klugmann et al., 1997) to study the effects of loss of Plp gene function on oligodendrocyte development and myelination in the central nervous system. Surprisingly the Plp gene knockout mouse showed no gross evidence of dysmyelination but did develop a late onset phenotype associated with progressive axonal changes. This study characterised the phenotype of these mice and assessed the ability of Plp gene isoforms to modify the phenotype of Plp gene knockout mice by transgenic complementation. The Plp gene knockout mouse formed large volumes of myelin and maintained oligodendrocyte numbers into adulthood. However, in the central nervous system, myelin was ultrastructurally abnormal and a proportion of small diameter axons failed to acquire myelin sheaths. Axonal changes consisted of swollen and degenerate axons and were confined to myelinated regions of the central nervous system where small diameter fibres appeared to be preferentially affected. Transgenic complementation with constructs expressing all of the components of the Plp gene ameliorated the phenotype of the Plp gene knockout mouse demonstrating that these changes were the direct result of loss of Plp gene function. These results indicate that, although the Plp gene products play roles in initiating myelination and in stabilising myelin lamellae, they are not vital components for oligodendrocyte development or myelin formation. The development of axonal changes appears to depend on the presence of myelin and demonstrates a potential role for the Plp gene in axoglial interaction. In addition, the changes in the Plp gene knockout mouse highlight the increasingly recognised role of gene dosage in the pathogenesis of Plp gene-related disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Ian Griffiths
Keywords: Genetics
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-75955
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 17:12
Last Modified: 19 Nov 2019 17:12
URI: http://theses.gla.ac.uk/id/eprint/75955

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