Myelin sheath is essential to normal conduction in nerves and is altered in multiple sclerosis and Guillain-Barre diseases. Underlying how myelin is formed and repaired requires basic studies of the differentiation of myelin-forming cells both in vitro and in vivo. Within the developing rat central nervous system (CNS), progenitor cells of oligodendrocytes are stimulated to divide by a factor secreted by Type I astrocytes. We are characterizing this mitogenic factor using a transformed cell line derived from rat CNS which produces a potent mitogenic activity for these progenitors. In a microculture system, a single neonatal progenitor cell in contact with a layer of Type I astrocytes produces a clone of oligodendrocytes containing a slowly dividing """"""""adult"""""""" type progenitor which may be able to repair myelin in the adult. We are also studying in vitro how defined populations of neurons influence the oligodendrocyte differentiation pathway. To further analyze the factors that control the development of the oligodendrocyte lineage at both the molecular and cellular level, we are using a rat myelin deficient mutant (sex-linked lesion) which fails to synthesize myelin protein gene mRNAs and appears to have a block in early oligodendrocyte differentiation. Finally, we are studying the regeneration of CNS myelin in a demyelinating disease (caused by a virus in mice). We have detected a widespread activation of myelin basic protein gene expression in the normal white matter surrounding the lesion using in situ hybridization. The regulation of expression of major myelin proteins in the CNS (PLP) and peripheral nervous system (PNS) (P-o) is another object of our investigation. We determined which domains of the PLP molecule are exposed to the extracellular space in living oligodendrocytes and compared hybrid Schwannoma cells to normal Schwann cells in vitro to analyze what blocks translation of P-o as well as MBP in the absence of neurons.
