Persistence of oligodendrocyte precursor cells and altered myelination in optic nerve associated to retina degeneration in mice devoid of all thyroid hormone receptors

Abstract

Thyroid hormone (3,5,3-triiodo-L-thyronine or T3) exerts a pleiotropic activity during central nervous system development. Hypothyroidism during the fetal and postnatal life results in an irreversible mental retardation syndrome. At the cellular level, T3 is known to act on neuronal and glial lineages and to control cell proliferation, apoptosis, migration, and differentiation. Oligodendrocyte precursor cells (OPC) found at birth in the optic nerves are self-renewing cells that normally differentiate during the first 3 weeks of rodent postnatal life into postmitotic myelinating oligodendrocytes. In vitro, the addition of T3 to OPC is sufficient to trigger their terminal differentiation. The present analysis of T3 receptor knockout mice reveals that the absence of all T3 receptor results in the persistence of OPC proliferation in adult optic nerves, in a default in myelination, and sometimes in the degeneration of the retinal ganglion neurons. Thus, T3 signaling is necessary in vivo to promote the complete differentiation of OPC. T hyroid hormone (3,5,3Ј-triiodo-L-thyronine, T3) acts directly at the transcription level by binding to nuclear receptors (TR␣1 and TR␤1, TR␤2, TR␤3) encoded by both TR␣ and TR␤ genes to control a number of physiological and developmental processes. During the late embryonic postnatal period, T3 action is critical for brain development. However, although both hyperthyroidism and hypothyroidism are known to affect directly or indirectly the proliferation, apoptosis, migration, and differentiation of several neuronal and glial cell types (1, 2), only subtle brain defects have been reported to date in the nervous system of TR knockout mice (3, 4). Moreover, knock-in point mutations recently led to contrasting results that are difficult to interpret (5-7). In the rodent optic nerves, oligodendrocyte precursor cells (OPC) differentiate during the first postnatal weeks to give rise to the oligodendrocytes that synthesize myelin around the axons of the retinal ganglion cells (RGC). The in vitro culture of newborn optic nerve OPC (8-10) has offered a unique opportunity to study the precise influence of T3 on the differentiation of this category of glial cells (reviewed in ref. 10). This in vitro model has been extensively investigated, and a number of studies confirmed the direct effect of T3 on OPC differentiation. However, the fact that retinoic acid or glucocorticoids can substitute to T3 to trigger in vitro OPC differentiation (9, 11) raises the question of the respective importance of these factors in vivo. The respective contribution of TR␣ and TR␤ in OPC hormonal response is also unclear (8,10,12). TR␣ is expressed at all stages of oligodendrocyte differentiation, whereas the status for TR␤ remains controversial. Based on RNA and protein analysis, TR␤ expression has been reported to be restricted to differentiated oligodendrocytes (13-16) or to occur in both OPC and oligodendrocytes (9, 17). To clarify the importance of T3 action in vivo and the respective functions of TR␣ and TR␤ in OPC...

Functional Identification of Neural Stem Cell–Derived Oligodendrocytes by Means of Calcium Transients Elicited by Thrombin

“…Indeed, Barres et al 1994 [22] increase the generation of oligodendrocytes from murine embryonic stem cells [24] as well as in human embryonic stem cells [25]. It seems that T3 not only accelerates the rate of oligodendrocyte precursor's generation but also the complexity of their morphology towards a mature oligodendrocyte [26] and the synthesis of myelin proteins [29,30]. As expected, we observed much more O4 as well as NG2 positive oligodendrocytes in the T3 treated cultures as compared to the non-treated cultures.…”

Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbers and Astrocyte Development in the Developing Retina

“…Consistent with this idea, Tlx KO retinal astrocytes have lost their expression of R-cadherin, a critical component of retinal vasculogenesis (Dorrell et al, 2002), but continue to express other astrocyte-specific proteins, including Pax2, PDGFR␣, and GFAP (Chu et al, 2001). Thus, Tlx might be involved in some aspects of differentiation and maturation of astrocytes, as is the case with the thyroid hormone receptor, another nuclear receptor that is involved in the terminal differentiation of oligodendrocyte precursor cells in the optic nerve (Baas et al, 2002).…”

Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease

“…Cell-cycle stopping mechanism, terminal differentiation, and myelin production require TH (19). Studies in genetically modified animals (20,21), such as the analysis of myelination in hypo-and hyperthyroid animals (22), have provided abundant evidence that TH plays an important part in regulating oligodendrocyte lineage and maturation also in vivo and that the TH receptor ␣1 seems to be responsible for this process (23).…”