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) he lps control this timing both in vitro and in vivo, but it is still uncertai n 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 recep tors 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 expressi on of two dominant-negative forms of TR beta1 greatly delays differentiatio n. Surprisingly, however, we find that postnatal TR beta-/- mice have a nor mal number of oligodendrocytes in their optic nerves and that TR beta-/- OP Cs stop dividing and differentiate normally in response to TH in vitro. Mor eover, 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 v ivo. This decrease may help control when oligodendrocyte precursors differe ntiate. (C) 2001 Academic Press.