An analysis of the early events when oligodendrocyte precursor cells are triggered to differentiate by thyroid hormone, retinoic acid, or PDGF withdrawal

Oligodendrocyte precursor cells withdraw from the cell cycle and terminally differentiate after a limited number of cell divisions. The timing of cell -cycle withdrawal and differentiation is controlled by an intrinsic timer, which consists of a timing component that measures elapsed time and an effe ctor component that arrests the cell cycle and initiates differentiation. T he effector component can be triggered by either thyroid hormone (TH) or re tinoic acid (RA). In this study we investigate how TH and RA act to trigger differentiation. We show the following: (1) Synthetic retinoids that can i nhibit AP-1 transcription factors but do not activate gene transcription ca nnot trigger the effector mechanism, suggesting that TH and RE do not act o nly by inhibiting AP-1 activity as previously suggested. (2) Both TH and RA induce a transcriptionally dependent antigenic change in purified precurso r cells within 2-4 h. (3) Unexpectedly, even before they differentiate, the precursor cells express ceramide galactosyltransferase (CGT), the enzyme t hat catalyzes the final step in the synthesis of galactocerebroside, an ear ly marker of oligodendrocyte differentiation. (4) Neither TH nor RA directl y activates the transcription of the CGT gene, a number of immediate early genes, or the genes that encode any of the known cyclin-dependent kinase in hibitors. (5) The withdrawal of the mitogen platelet-derived growth factor (PDGE), but not TH or RA treatment, causes a rapid decrease in c-fos, NGFI- A/Krox-24 and cyclin D2 mRNA, even though all three treatments trigger cell -cycle arrest and differentiation. (6) PDGE withdrawal and TH treatment, bu t not RA treatment, induce an increase in cyclin D3 mRNA within 4 h. Thus, we have not found any early changes in gene expression that occur with all three treatments that trigger oligodendrocyte differentiation. (C) 1999 Aca demic Press.