INHIBITION OF PROTEIN AND LIPID SULFATION IN OLIGODENDROCYTES BLOCKS BIOLOGICAL RESPONSES TO FGF-2 AND RETARDS CYTOARCHITECTURAL MATURATION, BUT NOT DEVELOPMENTAL LINEAGE PROGRESSION

We have examined the interfaces between protein and lipid sulfation, t he response of progenitor cells to specific growth factors, and develo pmental lineage progression. The experimental system used is the oligo dendrocyte (OL), the cell responsible for myelination of axons in the central nervous system. The ability to regulate the growth and differe ntiation of oligodendrocytes in primary cultures growing in defined me dium offers a particularly attractive model for these interrelated are as of cell and developmental biology. Sulfation was inhibited in this system by growing cells in sodium chlorate, a competitive inhibitor of sulfation. Four principal conclusions are drawn from the data. First, heparan sulfate proteoglycan is a necessary cofactor for the environm ental regulation by FGF-2 of nontransformed oligodendrocyte progenitor s, including both the mitogenic response and the inhibition of termina l differentiation at a specific stage of the lineage. Second, the diff erentiation of oligodendrocyte progenitors from an early to a mature s tage can occur in the absence of sulfation. Third, however, the format ion of cellular processes and myelin-like sheets is retarded, leading to the prediction that sulfated molecules are critically involved in a spects of oligodendrocyte differentiation directly relating to myelina tion per se. Fourth, the developmental proligodendroblast antigen, POA , is a sulfated molecule. The results provide clear evidence for the i mportance of sulfation for the responses of OL progenitors to FGF-2 an d for OL cytoarchitectural maturation, while demonstrating an ability of OL progenitors to undergo lineage progression in its absence. (C) 1 994 Academic Press, Inc.