The myelin sheath is essential for normal conduction in major nerve tracks. Therefore neurological dysfunction occurs in demyelinating diseases such as multiple sclerosis (MS) and viral encephalitis, We study how myelin-forming cells of the CNS, the oligodendrocytes, can develop and regenerate both in vitro and in vivo. We analyze the role of neuronal and glial-derived growth factors in the mitosis, migration and differentiation of the progenitors of oligodendrocytes. Neonatal progenitors in culture proliferate in the presence of bFGF and remain undifferentiated as assessed by the expression of a POU-homeodomain protein (Oct-6) and the high levels of PDGF alpha receptors. Such progenitors respond to PDGF by mitosis, migration and eventually, expression of myelin genes accompanied by a downregulation of PDGF alpha receptors and Oct-6 transcripts. Both IGF1 and TGFbeta may promote this pathway of differentiation. TGFbeta 1,2,3 isoforms are all expressed in oligodendrocytes while progenitor cells express only TGFbeta1. A small number of progenitor cells persist in the adult myelinated CNS of rodents and mean which do not respond to known growth factors by mitosis but can become oligodendrocytes and are therefore called pre-oligodendrocytes. As with neonatal progenitors, differentiation of """"""""pre-oligodendrocytes"""""""" is enhanced by IGF1 and inhibited by bFGF. After a demyelinating event in mice, many cells of the oligodendrocytes lineage proliferate and migrate to repair demyelinating lesions. To characterize the signals which stimulate myelin repair in vivo, we graft into demyelinated recipient animals glial cells from transgenic mice expressing a constitutive or inducible gene in the oligodendrocyte lineage. These studies may pave the way to the design of strategies to enhance remyelination in demyelinating diseases.
