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, alpha and beta, encode different isoforms, of which only the beta and alpha1 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 alpha1 and alpha2 isoforms, but the expression of the beta1 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 alpha1 NT3R and its variant alpha2, but not that of the beta1 isoform, in newborn rat glial progenitors. The pattern of expression of beta1, 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 alpha to the beta1 isoform. Thus, the expression of NT3R isoforms in the rat oligodendrocyte lineage changes radically from the alpha to the beta1 isoform during the period when oligodendrocytes differentiate from progenitors.

Combined effects of transferrin and thyroid hormone during oligodendrogenesis In vitro

“…There appears to be general consensus that both OPCs and OLGs express TRα and that OLGs express TRβ (Carré et al, ; Fierro‐Renoy, 1995), in agreement with Bury et al (), who showed that TRα and TRβ colocalize in OLGs before CNPase is expressed. Very recently, Baxi et al () showed that a TRβ agonist promotes oligodendrogenesis in rodents and in human OPCs in vitro .…”

Thyroid hormones states and brain development interactions

“…Furthermore, thyroid hormones, acting through thyroid hormone receptors (TRs) and play an important role in amphibian metamorphosis and vertebrate development (Nagasawa et al, 1997). These receptors are expressed in neurons, oligodendrocytes, and astrocytes, the predominant cell types in the brain (Mellström et al, 1991; Strait et al, 1991, 1997; Bradley et al, 1992; Carlson et al, 1994; Carre et al, 1998). Taking into account that thyroid hormone exerts specific effects on brain development by regulating gene expression (Oppenheimer and Schwartz, 1997; Zhang and Lazar, 2000), some studies demonstrate that several genes are regulated directly by thyroid hormones at the transcriptional level and at an earlier stage of cerebellar development, i.e., during embryonic day 18–postnatal day 0 (Alvarez‐Dolado et al, 1999).…”

Normal timing of oligodendrocyte development depends on thyroid hormone receptor alpha 1 (TRalpha1)

“…Although developing rat OPCs seem not to express the TR β gene (Baas et al ., 1994a,b; Carre et al ., 1998), we previously showed that overexpression of TRβ1 in these cells accelerated their differentiation in the presence of PDGF and TH (Billon et al ., 2001). These findings are consistent with our present results, as TRβ1 and TRα1 can bind to the same TREs and recruit some of the same co‐regulatory proteins.…”