GLIAL TRANSPLANTS - AN IN-VIVO ANALYSIS OF EXTRINSIC AND INTRINSIC DETERMINANTS OF DYSMYELINATION IN GENETIC-VARIANTS

Myelination in the CNS depends on the ability of oligodendrocytes (Ols ) to efficiently colonize the brain, differentiate, and express a prec ise balance of specific genes necessary for myelin synthesis. Mutation s in these genes produce different types of dysmyelinisation in animal as in human. Defects in the synthesis of myelin constituents usually lead to mild dysmyelinations. In contrast, mutations affecting the gen e encoding the proteolipid, another major protein of myelin, produce v arious perturbations of Ols biology suggesting a pleiotropic effect of the gene in the development of the CNS. Studies on expansion of cell population and survival have provided contradictory information on the extrinsic and intrinsic action of the gene on Ols biology. On one han d, in vitro studies using conditioned media as in vivo studies on hete rozygotes, and transplantations experiments suggest that excess of pro grammed cell death in these mutants is ruled out by intrinsic factors which could act during embryonic life. On the other hand, attempts to compensate the gene defect by transgenic correction demonstrate a domi nant negative effect of the jp mutation on both survival and functiona l potential of Ols. Finally, total suppression of PLP gene expression has a restricted effect on myelin structure without excess of cell dea th. These contradictory results are discussed in the perspective of re gulation of cell death by competition for growth factors in limiting a mount. The proposed model suggests that this contradiction is only app arent, and that excess of cell death in PLP/DM20 mutant is intrinsical ly determined by diminished competitivity of the mutant Ols for limite d amounts of environmental factors.