抄録
Human leukodystrophies are hereditary and incurable dysmyelinating diseases. Their precise diagnosis and therapy must be studied using model animals. There is increasing interest in hereditary dysmyelinating mutant mice such as jimpy, quaking, twitcher, shiverer and myelin deficient (mld), as animal models for human leukodystrophies. Even though some of these mutants do not share the same enzymatic disturbances as human leukodystrophies, they are nice models of“dysmyelinating”diseases. Furthermore, they are also useful tools to analyze the genetic control and the intercellular (neurone-glial) recognition process of the myelination. We have intensely analyzing the dysmyelinating mutant mice designated as shiverer and myelin deficient (mld) . Both mutants have been revealed that they are disturbed in the expression of myelin basic protein (MBP) . MBP is one of major stractual proteins of the myelin. So shiverer and mld are good systems to analyze the relation between the regulation of MBP gene expression and the morphogenesis of myelin. Shiverer is an autosomal recessive mutant characterized by abnormal and poor myelin formation in the central nervous system accompanying severe tremor and tonic convulsions. Myelin of the shiverer has been proved to lack MBP by SDS-PAGE protein profile and immunohistochemical studies. We have used mice which have different strain specific isozyme pattern of GPI as wild type control. Brain tissue of chimeras examined is composed of both isozymes as well as coat color. By immunohistochemical staining of MBP, patches of MBP-negative and -positive sites are observed in the white matter of chimeras suggesting the absence of humoral factors to cause abnormal myelin formation. Shiverer-type myelin is observed adjacent to the normal myelin on the same axon, suggesting that oligodendrocyte itself would be responsible for the abnormal and poor myelination in the shiverer central nervous system. Kimura et al. have revealed shiverer has deletion mutation in MBP gene by Southern-blot analysis using MBP cDNA as a probe.
Mld displays similar findings to shiverer and shows the allelism to shiverer. In mld, too, remarkably reduced amount of MBP can be observed in SDS-PAGE protein profile. By immunohistochemical staining of MBP, scattered MBP-positive sites are slightly detectable in mld. This is the different point from shiverer. Molecular genetic analysis studies using MBP cDNA as a probe show the prominent decrease of myelin basic protein (MBP) in mld is based on the transcriptional level and MBP gene of mld has no significant changes compared with wild type control in the exons.
