Hubank, Michael John Francis; (1990) Biochemical effects and molecular mechanisms of thyroid hormone action in the developing rat brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Evidence has recently accumulated favouring the notion that maternal thyroid hormones (TH), specifically T4, traverse the placenta from mother to fetus during pregnancy and exert influences critical to normal fetal brain development. The aim of this project was to assess whether lack of T4 transfer resulted in any alterations to the biochemical systems of the fetal brain, and if so, to attempt to identify some of the molecular mechanisms responsible. The progeny of hypothyroxinemic rat dams demonstrated organ-specific reductions in weight and protein content during the neonatal period, after which compensation took place. In the brains of the progeny, specific reductions were observed in the levels, localisation, and temporal expression of a number of Con A binding glycoproteins both in membranes and in the cytosol. The activities of certain lysosomal enzymes were also found to be reduced. T3 stimulated the incorporation of [3H]-fucose into glycoproteins in astrocytic cultures, where it became concentrated in the plasma membrane. Time course experiments suggested that regulation occurs at the transcriptional rather than translational level. It is therefore possible that TH is involved in the regulation of neurogenesis partly via controlling the expression of cell-surface glycoproteins. A study of the ontogeny of TH binding to nuclear receptors in separated neuronal and glial nuclei from different regions of neonatal rat brain revealed high levels of binding in both neurons and glia which diminished with age. An early postnatal peak in receptor number was due to high levels in the glia. A significant neonatal increase was also noticed in the affinity of the receptor for hormone in glial nuclei. It is suggested that this may be evidence for the presence of at least two types of receptor, which are expressed in a temporally-controlled, and possibly cell specific manner, and may be involved in co-ordination of TH action on the developing brain.

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