Proteolipid protein regulates the survival and differentiation of oligodendrocytes

Proteolipid protein (PLP) has been postulated to play a critical role in the early differentiation of oligodendrocytes (OLs) in addition to its known role as a structural component of myelin. To identify this early function, we blocked the synthesis of PLP in glial cultures with antisense oligodeoxynucleotides that targeted the PLP initiation codon. Primary glial cultures were incubated with phosphorothioate-protected oligodeoxynucleotides (S-ODNs) for up to 11 d. PLP in OLs was reduced >90%. OLs treated with antisense S-ODNs appeared strikingly healthy as judged by (1) immunocytochemical staining for myelin glycolipids and myelin basic protein, (2) their prolonged survival compared with untreated cultures, and (3) their ability to re-establish membrane sheets after removal of the S-ODNs. Our studies show that PLP is required for elaboration and stability of the myelin membrane sheets made by most OLs, but it is not necessary for the network of processes established by OLs. More importantly, the number of OLs in the antisense-treated cultures was nearly sevenfold greater after a 10-11 d incubation with S-ODNs than in control cultures. The number of proliferating OL progenitors was not increased in the antisense-treated cultures, indicating that the increase in the number of OLs was attributable to prolonged OL survival. The tissue culture studies reveal that the absence of PLP/DM20 has the positive effect of promoting OL survival but the negative effect of preventing their full differentiation. This finding clarifies many of the paradoxical findings seen in the PLP mutants, the PLP overexpressers, and the PLP- animals.