Role of thyroid hormone receptors in timing oligodendrocyte differentiation

The timing of oligodendrocyte differentiation is thought to depend on both intracellular mechanisms and extracellular signals. Thyroid hormone (TH) helps control this timing both in vitro and in vivo, but it is still uncertain how it does so. TH acts through nuclear receptors that are encoded by two genes, TR alpha and TR beta. Previous studies suggested that TR beta receptors may mediate the effect of TH on oligodendrocyte precursor cells (OPCs). Consistent with this possibility, we show here that overexpression of TR beta1 promotes precocious oligodendrocyte differentiation, whereas expression of two dominant-negative forms of TR beta1 greatly delays differentiation. Surprisingly, however, we find that postnatal TR beta-/- mice have a normal number of oligodendrocytes in their optic nerves and that TR beta-/- OPCs stop dividing and differentiate normally in response to TH in vitro. Moreover, we find that OPCs do not express TR beta1 or TR beta2 mRNAs, whereas they do express TR alpha1 and TR alpha2 mRNAs. These findings suggest that alpha receptors mediate the effect of TH on the timing of oligodendrocyte differentiation. We also show that TR alpha2 mRNA, which encodes a dominant-negative form of TR alpha, decreases as OPCs proliferate in vitro and in vivo. This decrease may help control when oligodendrocyte precursors differentiate. (C) 2001 Academic Press.