IS THYROID-HORMONE A CLOCK-GOVERNING HORM ONE DURING THE DEVELOPMENT OF THE CENTRAL-NERVOUS-SYSTEM

The development of the nervous system follows two models: the instruct ive or clonal model (expression of genetic information) and the select ive model (regulation during a critical period of gene expression by h ormones or growth factors (auto-selective), or by epigenetic factors s uch as nutrition, environment, etc.). The two processes that character ize development, proliferation and cell differentiation, are regulated independently. The alpha receptor of T3 (alpha T3R) is constitutively expressed in neuronal and glial cell lines. Without T3, or in the pre sence of T3 but in the absence of transcription factors likely to form heterodimers with this receptor (e.g. the alpha RXR receptor of 9-cis -retinoic acid), growth factors (PDGF, NGF, NT-3, IGF) do regulate the mitotic activity of neuroblasts and glioblasts. The presence of T3 (r esulting from the onset of thyroid activity and from the increased tis sue capacity for deiodation of T4) and (or) the appearance of transcri ption factors likely to interact with RT3 alpha to form a functional h ormone-receptor unit, leads to blocking of the cell cycle; it then ini tiates cell differentiation, probably by inhibiting the AP1 complex, w hich induces mitotic activity and represses differentiation in many ce ll types. The action of T3 is followed by spatial coordination of the establishment of the synaptic network, in parallel with temporal regul ation of cell differentiation (cytoskeletal development and neuritogen esis) and of the survival (apotosis) of its constitutive elements. Con comitantly, T3 controls the appearance of, or the overexpression of, i ts beta receptor. Thyroid hormone plays an essential role in the tempo ral regulation of proliferation, differentiation and cell survival, di rectly and (or) in a permissive way via growth factors and neurotrophi ns, the synthesis of which is hormone-dependent. This makes it one of the determinant neurotropic factors involved in the structural reorgan ization and functional adaptations that characterize the plasticity of the developing nervous tissue.