title: Murine leukodystrophies as tools to study myelinogenesis in normal and pathological conditions.
abstract: Myelinogenesis is controlled by several genes. Therefore, the study of mutations affecting myelination should provide better understanding of the assembly and maintenance of myelin, and in the case of similitude with human diseases, a direct insight into the pathogenesis of these diseases. Murine mutants can be bred readily and sequential analyses allow an examination of the dynamic processes of myelination. In this study, we have selected certain aspects of four leukodystrophies in mice. The precise mechanisms leading to the important myelin deficit observed in the jimpy mutation, a sex-linked recessive trait, are still not completely elucidated. Our results show in jimpy mice severe astrocytic alterations prior to myelin formation. Therefore, abnormalities of oligodendrocytes and possibly axons could be a secondary phenomenon. Nevertheless, a defect involving neuroglia precursor cells cannot be ruled out. At the present time, Pelizaeus-Merzbacher is a disease in which mainly oligodendrocytes appear to be altered. In consequence, our findings in jimpy mice do not support the present contention that this mutation represents a model for Pelizaeus-Merzbacher disease. We propose that the jimpy mutation could be invaluable to study cell-cell interactions at an early stage of myelinogenesis. Interest in the myelin deficient (mld) mutant derives from the specific lack of one of the major myelin constituents, myelin basic protein, and the concomitant absence of the major electron dense line during the active phase of myelin deposition in the CNS. Our present knowledge points out a defect of gene regulation involving myelin basic protein synthesis. The absence of this extrinsic membrane component made it possible to catch a glimpse of its role in the formation and maintenance of the complex structure of the myelin sheath in the CNS. Quaking mice have been considered to represent an arrest of myelinogenesis. This commonly accepted view has to be reconsidered at the light of recent morphological and biochemical findings. An abnormal processing of the myelin-associated glycoprotein could prevent the normal compaction of myelin until the animals reach adulthood. Twitcher is characterized by extensive central and peripheral demyelination and the presence of intracellular inclusions in macrophages similar to human globoid cell leukodystrophy. In both human and murine diseases, a deficiency of galactosylceramidase activity was demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000648:ultrastructure; D001369:Axons / Q000648:ultrastructure; D001921:Brain / Q000473:pathology; D002648:Child; D005614:Freeze Fracturing; D005698:Galactosylceramidase / Q000172:deficiency; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000648:ultrastructure*; D009413:Nerve Fibers, Myelinated / Q000648:ultrastructure; D009836:Oligodendroglia / Q000648:ultrastructure
chemical_list: D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D005698:Galactosylceramidase