New Insights into Thyroid Hormone Action in the Developing Brain: The Importance of T3 Degradation

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Thyroid hormone (TH) is essential for normal development and for normal metabolic and physiological function throughout life. But this general statement does not capture the complexity of TH action. For example, during development, TH appears to control fate specification (1) and migration (2–4) of early neuroblasts in the cerebral cortex but does not appear to influence their proliferation (5). In contrast, TH clearly controls proliferation, migration, and apoptosis of cerebellar granule cells (6,7).Moreover,THcontrolssynaptogenesisinthecortex andhippocampus(8,9),developmentofspecificelements of the cochlea (10), differentiation of specific photoreceptors in the retina (11), the balance of production of oligodendrocytes and astrocytes in bridging white matter (12),andmanyotherspecificfeaturesofdevelopment.But TH does not produce all of these effects simultaneously; rather, these events occur in an orderly sequence. Thus, a key feature of TH action is the temporal sequence of events it supports, and this conclusion provides essential clues about mechanisms controlling TH action. Forexample,expansionanddifferentiationofthecerebral cortex occur early in fetal development when the cerebellum is quiescent. Later, with these events in the cerebrum completed, the cerebellum begins to expand and differentiate under TH control. However, TH levels in maternal andfetalbloodarenotdifferentduringthesedevelopmental stages. These observations dictate that there must be tissue-level mechanisms controlling the sensitivity to TH, and this sensitivity must change during the course of development both within different cells in a single tissue and across tissues.