Effects of thyroid hormones during brain differentiation

Abstract

Since the placenta is practically impermeable to thyroid hormones (Fisher et al., 1977), the foetus depends for its brain development on the activity of its own thyroid gland: thyroid hormone deficiency at birth leads to severe physiological, biochemical and behavioural defects (Shapiro, 1977) which can be corrected only if an adequate replacement therapy is performed as early as possible. The most dramatic effects of thyroid hormones take place during the critical period of brain development, i.e. when the cell ceases to divide and begins to differentiate. Although several other abnormalities are observed in neonatal hypothyroidism (for instance defective myelination), probably the most significant of them is a hypoplastic neuropile, i.e. a reduction in electric activity of the brain and in the number of interactions between neurons (Eayrs, 1960; Legrand, 1967). A large variety of neuronal cell types is produced during brain differentiation and each mature neuron seems to be unique in its function. It therefore appears very difficult to expect that detailed studies will allow the description, in the near future, of how the differentiation programme allows the specification of the expression of each neuron. However, all neurons undergo a common major morphological transformation during brain differentiation, i.e. the formation of nerve cell processes which extend from the cell body to produce the dendrites and the axons. Such a dramatic change in cell shape is probably under thyroid hormone control and it seems to correlate well with the reduction in the number of connections seen in hypothyroidism. Changes in cell shape appear more and more directly related to both fast and slow modifications in the organisation of the cytoskeleton. This conclusion seems to apply not only to nerve cells but also to a variety of other cell types. In several of these systems thyroid hormones are required together with other factors to achieve complete maturation. Changes in the composition and organisation of the different elements which contribute to the building-up of the cytostructure are also good markers of neuronal cell differentiation, since neurite outgrowth not only implies large modifications in shape but also forward development of the growing processes. In this survey we shall successively and briefly describe (1) the aspects of the primary mechanism of action of thyroid hormones which have been found to be common to nerve cells and other cell types; (2) the different in vivo effects of thyroid hormone on the various parameters of brain development; (3) some of our recent attempts to ex$G-i on a biochemical basis the effects of thyroid hormones on neurite outgrowth. No attempt has been made to refer to all articles published on these topics. A more detailed review is in press in the new edition of the Handbook of Neurochemistry (Nunez, 1984).