Two molecularly distinct intracellular pathways to oligodendrocyte differentiation: role of a p53 family protein

Both thyroid hormone (TH) and retinoic acid (RA) induce purified rat oligod endrocyte precursor cells in culture to stop division and differentiate. We show that these responses are blocked by the expression of a dominant-nega tive form of p53. Moreover, both TH and RA cause a transient, immediate ear ly increase in the same 8 out of 13 mRNAs encoding intracellular cell cycle regulators and gene regulatory proteins, but only if protein synthesis is inhibited. Platelet-derived growth factor (PDGF) withdrawal also induces th ese cells to differentiate, but we show that the intracellular mechanisms i nvolved are different from those involved in the hormone responses: the cha nges in cell cycle regulators differ, and the differentiation induced by PD GF withdrawal (or that which occurs spontaneously in the presence of PDGF) is not blocked by the dominant-negative p53. These results suggest that TH and RA activate the same intracellular pathway leading to oligodendrocyte d ifferentiation, and that this pathway depends on a p53 family protein. Diff erentiation that occurs independently of TH and RA apparently involves a di fferent pathway. It is likely that both pathways operate in vivo.