Abstract
The consequences of dysmyelination are poorly understood and vary widely in severity. The shaking mouse, a quaking allele, is characterized by severe central nervous system (CNS) dysmyelination and demyelination, a conspicuous action tremor, and seizures in approximately 25% of animals, but with normal muscle strength and a normal lifespan. In this study we compare this mutant with other dysmyelinated mutants including the ceramide sulfotransferase deficient (CST-/-) mouse, which are more severely affected behaviorally, to determine what might underlie the differences between them with respect to behavior and longevity. Examination of the paranodal junctional region of CNS myelinated fibers shows that "transverse bands," a component of the junction, are present in nearly all shaking paranodes but in only a minority of CST-/- paranodes. The number of terminal loops that have transverse bands within a paranode and the number of transverse bands per unit length are only moderately reduced in the shaking mutant, compared with controls, but markedly reduced in CST-/- mice. Immunofluorescence studies also show that although the nodes of the shaking mutant are somewhat longer than normal, Na(+) and K(+) channels remain separated, distinguishing this mutant from CST-/- mice and others that lack transverse bands. We conclude that the essential difference between the shaking mutant and others more severely affected is the presence of transverse bands, which serve to stabilize paranodal structure over time as well as the organization of the axolemmal domains, and that differences in the prevalence of transverse bands underlie the marked differences in progressive neurological impairment and longevity among dysmyelinated mouse mutants.