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Quantitative differences between homozygous 'USA' and 'Swiss' mld mutant mice
S Billings-Gagliardi1, M Tosic, J M Matthieu
1Department of Cell Biology, University of Massachusetts Medical School, Worcester.
Abstract:
Parallel developmental studies of central nervous system myelin proteins and morphology (postnatal days 15-118; P15-118) confirm qualitative similarities but substantial quantitative differences between homozygous mld mice with Billings-Gagliardi and Wolf's 'USA' versus Matthieu's 'Swiss' genetic backgrounds. The USA mld/mld have fewer convulsions and significantly longer life span. While whole-brain homogenates from both Swiss and USA mld/mld show increases in myelin basic protein (MBP) and in 2',3'-cyclic nucleotide 3'-phosphohydrolase specific activity with age, at P50 and older the levels of both proteins are approximately twice as high in the Swiss. The number of optic nerve axons myelinated is always greater in Swiss mld/mld, and they have approximately twice as many myelin sheaths showing any apposition of cytoplasmic membrane faces (the location of the major dense line in normal myelin), except at the youngest age. Evidence is presented which suggests that these quantitative differences between Swiss and USA mld stocks most likely reflect different regulatory genes influencing the expression of the same (mld) allele, rather than the presence of a different allele at the MBP locus.
Insights
Genetic background significantly impacts myelin development in mld mice. Differences in regulatory genes, not the myelin basic protein (MBP) locus, explain quantitative variations in myelin proteins and morphology.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- The myelin deficient (mld) mouse model is crucial for studying myelin disorders.
- Quantitative differences in mld mouse phenotypes have been observed across different genetic backgrounds.
Purpose of the Study:
- To investigate the impact of genetic background on central nervous system myelin development in mld mice.
- To compare myelin protein levels and morphology in mld mice from 'USA' and 'Swiss' genetic backgrounds.
Main Methods:
- Developmental studies of myelin proteins and morphology from postnatal day 15 to 118.
- Analysis of myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphohydrolase specific activity in brain homogenates.
- Morphological assessment of optic nerve myelination and myelin sheath structure.
Main Results:
- Homozygous mld mice on the 'USA' genetic background exhibit fewer convulsions and a longer lifespan compared to 'Swiss' mld/mld mice.
- While both strains show age-related increases in MBP and 2',3'-cyclic nucleotide 3'-phosphohydrolase, 'Swiss' mld/mld mice have approximately double the levels post-P50.
- The 'Swiss' mld/mld mice consistently show more myelinated optic nerve axons and twice as many myelin sheaths with membrane apposition.
Conclusions:
- Quantitative differences in myelin development between 'USA' and 'Swiss' mld mouse stocks are significant.
- These variations likely stem from regulatory genes affecting the expression of the mld allele, rather than alterations at the MBP locus.