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Updated: Sep 7, 2026
Conditional Genetic Transsynaptic Tracing in the Embryonic Mouse Brain
Published on: December 22, 2014
Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation
Abstract:
Shiverer (shi) is an autosomal recessive mutation in the mouse characterized by an almost total lack of central nervous system myelin. While small amounts of other myelin components are present in the brain of the shi mouse, the four forms of myelin basic protein (MBP) are not detectable. Previous investigations by us and others indicate that the MBP gene has undergone a major rearrangement in the shi mutant. Herein, we report in detail the nature and extent of the rearrangement: a 20-kilobase region within the MBP gene is missing in the mutant. We map the 5' breakpoint of the deletion to the second intron and the 3' breakpoint to a site 2 kilobases beyond the last MBP exon. The junction of the upstream and downstream portions of the gene contains only one nucleotide not accounted for by the wild-type MBP gene sequence. The 3' side of the deletion occurs in the 3rd of 11 tandem repeats of a 31-base-pair sequence. This region is rich in alternating purine and pyrimidine stretches, sequences that have been associated with both Z-DNA structures and gene rearrangements. The recombination junction shares several features with the junctions characterized by Anderson et al. [Anderson, R., Kato, S. & Camerini-Otero, D. (1984) Proc. Natl. Acad. Sci. USA 81, 206-210] in mouse L cells and is consistent with their model for a partially homologous recombination event. The structure of the shi recombination junction suggests that the donor DNA molecules were aligned in a partially homologous region before staggered cutting and joining occurred.
Insights
The shiverer (shi) mouse mutation causes a severe lack of central nervous system myelin due to a 20-kilobase deletion in the myelin basic protein (MBP) gene. This gene rearrangement explains the absence of MBP and resulting myelin deficiency.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The shiverer (shi) mutation in mice results in a near-complete absence of central nervous system (CNS) myelin.
- Myelin basic protein (MBP) is a critical component of CNS myelin, and its four forms are undetectable in shi mutant brains.
- Previous studies suggested a significant rearrangement within the MBP gene in shi mutants.
Purpose of the Study:
- To precisely characterize the molecular nature and extent of the MBP gene rearrangement in the shiverer (shi) mouse mutant.
- To elucidate the genetic mechanism underlying the myelin deficiency observed in shi mice.
Main Methods:
- Detailed molecular analysis of the myelin basic protein (MBP) gene in shiverer (shi) mutant mice.
- Mapping of the 5' and 3' breakpoints of the deletion within the MBP gene.
- Sequence analysis of the recombination junction to identify structural features and potential mechanisms.
Main Results:
- A 20-kilobase deletion within the MBP gene was identified in shi mutant mice.
- The 5' breakpoint was mapped to the second intron, and the 3' breakpoint was located 2 kilobases downstream of the final MBP exon.
- The deletion junction contained a region rich in alternating purine-pyrimidine sequences, associated with Z-DNA and gene rearrangements, and exhibited features consistent with a partially homologous recombination event.
Conclusions:
- The extensive deletion within the MBP gene is the direct cause of the absence of MBP and the severe myelin deficiency in shiverer (shi) mice.
- The recombination junction structure suggests a model of partially homologous recombination, involving alignment in a homologous region followed by staggered cutting and joining.
- Understanding this specific gene rearrangement provides insights into the mechanisms of DNA recombination and their role in genetic mutations affecting neurological development.
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