Normal timing of oligodendrocyte development depends on thyroid hormone receptor alpha 1 (TRα1)

Abstract

The timing of oligodendrocyte development is regulated by thyroid hormone (TH) in vitro and in vivo, but it is still uncertain which TH receptors mediate this regulation. TH acts through nuclear receptors that are encoded by two genes, TRα and TRβ. Here, we provide direct evidence for the involvement of the TRα1 receptor isoform in vivo, by showing that the number of oligodendrocytes in the postnatal day 7 (P7) and P14 optic nerve of TRα1-/- mice is decreased compared with normal. We demonstrate that TRα1 mediates the normal differentiation-promoting effect of TH on oligodendrocyte precursor cells (OPCs): unlike wild-type OPCs, postnatal TRα-/- OPCs fail to stop dividing and differentiate in response to TH in culture. We also show that overexpression of TRα1 accelerates oligodendrocyte differentiation in culture, suggesting that the level of TRα1 expression is normally limiting for TH-dependent OPC differentiation. Finally, we provide evidence that the inhibitory isoforms of TRα are unlikely to play a part in the timing of OPC differentiation.