Quaking shiverer double mutant mice: morphological phenotypes support possible dual actions of the shiverer locus.

Mice doubly homozygous for the two different hypomyelination mutations, quaking (qk) and shiverer (shi) or shiverer myelin-deficient (shimld) (abbreviations: qk*shi and qk*shimld), both have much less myelin than either single mutant ancestor, myelin morphology resembling shi or shimld rather than qk, and abundant shi-type oligodendrocytic microprocesses. The qk*shimld double mutant differs from qk*shi only in having small amounts of normal or abnormal major dense line, in keeping with the morphologic difference between the shi and shimld single mutants. By contrast, shi*jp and shimld*jp have clearly different morphological phenotypes; unexpectedly the major dense line is present in the CNS myelin of shi*jp but not shimld*jp. When shi and shimld act alone, their different DNA abnormalities produce similar protein abnormalities. We speculate that the two mutations interact with qk at a different, later step of DNA expression than they interact with jp. In the interaction with qk, the similar proteins produce similar morphologies. In the interaction with jp, the different DNAs are somehow caused to produce protein differences that are reflected in different morphologies. In this study we have observed for the first time a morphological effect of these mutant genes in heterozygous animals. Of particular importance, animals whose genomes combine shi/+ or shimld/+ with qk/qk produce qk-type, compacted myelin but abundant shi-type oligodendrocyte microprocesses. We consider this as evidence that both shi and shimld have two effects: non-production of a normal structural protein, myelin basic protein, and production of an abnormal protein which perturbs the cytogogic function we postulate to be normally exercised by the myelin basic protein gene.