Thyroid hormone receptor isoforms are sequentially expressed in oligodendrocyte lineage cells during rat cerebral development

Abstract

In the mammalian brain, thyroid hormones regulate myelination. Their actions are mediated by interactions with nuclear receptors that function as ligand-regulated transcription factors. Two genes, α and β, encode different isoforms, of which only the β and α1 isoforms are authentic nuclear triiodothyronine (T3)-receptors (NT3R). In agreement with the important role of T3 on myelination and oligodendrocyte generation, the presence of NT3Rs has been reported in oligodendrocytes and their precursors. We and others have shown that both progenitors and oligodendrocytes in vitro express the α1 and α2 isoforms, but the expression of the β1 isoform is confined to differentiated oligodendrocytes, suggesting that they have different functions. To establish if this is the case during development in vivo, we have studied NT3R isoform expression in glial cells isolated by density gradient centrifugation from rat brains of various ages. We report the presence of the α1 NT3R and its variant α2, but not that of the β1 isoform, in newborn rat glial progenitors. The pattern of expression of β1, both at the level of mRNA and protein, parallels the increase in the number of oligodendrocytes. We found a significant change in the kinetic parameters of [125I]-T3 binding to NT3Rs in these cells during the first month of life, consisting of an increase in the binding capacity that peaks with myelination, and a significative decrease in Kd that coincides with the switch from the α to the β1 isoform. Thus, the expression of NT3R isoforms in the rat oligodendrocyte lineage changes radically from the α to the β1 isoform during the period when oligodendrocytes differentiate from progenitors.INSERM/CSIC de coopération biomédicale franco-espagnole.Peer Reviewe